American Journal of Medical Genetics Part C (Seminars in Medical Genetics) (2011)
A R T I C L E
Teratogenic Exposures
SARAH OBIČAN* AND ANTHONY R. SCIALLI
A consideration of teratogenic exposures includes not only an agent (chemical, radiation, biologic) but an
exposure level and timing of exposure. There are criteria by which exposures are evaluated for a causal connection
with an abnormal outcome. We here review some teratogenic exposures and discuss how they were initially
described and conﬁrmed. We have limited our discussion to some of the exposures for which a connection to
structural malformations has been accepted in some quarters, and we indicate some exposures for which a causal
association awaits conﬁrmation. We recommend that counselors ﬁnd a reliable and updatable source of
information on exposures during pregnancy. ß 2011 Wiley-Liss, Inc.
KEY WORDS: teratogenic exposures; angiotensin converting enzyme inhibitors; carbamzepine; diethylstilbestrol; ethanol; isotretinoin;
lithium; methimazole; misoprostol; mycophenolate mofetil; penicillamine; phenytoin; rubella; thalidomide; toluene; valproic acid; varicella;
warfarin; X-ray
How to cite this article: Običan S, Scialli AR. 2011. Teratogenic exposures.
Am J Med Genet Part C Semin Med Genet
INTRODUCTION
Authors who propose to write a paper on
teratogenic exposures owe their readers
answers to some basic questions, questions that have been posed for decades
and for which there are no entirely
satisfying answers. First, what is a
teratogenic exposure? Notice that we
have avoided the term, ‘‘teratogen,’’
which implies that a chemical or other
agent might have some property of being
teratogenic or non-teratogenic. We use
the term, ‘‘teratogenic exposure’’ to
include not only an agent but also
exposure level (dose) and timing considerations. We are fearful of listing
X-ray, for example, as a teratogen and
having someone give poor advice to a
woman who had a chest X-ray in early
pregnancy.
When we write teratogenic exposure, we mean an exposure that increases
the risk of an end point called, ‘‘teratogenicity,’’ but what is included in
teratogenicity? Certainly, we would
include malformations that can be diag-
nosed on physical examination in a
child, but other kinds of developmental
toxicity, such as functional impairment,
growth restriction, or impaired viability
are also important.
This paper is an overview of selected exposures. If you are in the counseling
business, you need a resource to provide
more detailed and current information
on a larger range of agents than we will
discuss. We can recommend TERIS
(http://depts.washington.edu/terisweb/
teris/) and Reprotox1 (www.reprotox.
org). We both work for Reprotox1.
A ﬁnal question: Who gets to
decide what exposures are teratogenic?
These decisions are made by the teratology community, but not everyone in
the teratology community agrees about
everything all the time. We use criteria
similar to or derived from those articulated by Hill [1965], shown in Table I.
Not all criteria need to be satisﬁed
for an association to be considered
causal, but the more criteria, the greater
our comfort that we are dealing with
causality.
It has been proposed that many
human teratogenic exposures have been
identiﬁed by ‘‘astute clinicians,’’ essentially from observing cases of distinctive
malformations associated with unusual
exposures [Carey et al., 2009]. Our
discussion of some teratogenic exposures
would seem to conﬁrm the impression
that identiﬁcation of teratogenicity
arises from the reports of astute clinicians; however, a key part of this astute
clinician model is that the initial observations are subsequently conﬁrmed by
other evidence. The clinicians who
made the initial observations may or
may not be astute, but they are certainly
lucky in having their observations conﬁrmed. We hear nothing about those
observations of birth defect syndromes
that went unconﬁrmed and have
vanished from the literature.
In some cases, we are left with
observations that have been inadequately conﬁrmed but that still deserve some
attention. We are in favor of counseling
patients about exposures even if risk
has not been conﬁrmed. For example,
Sarah Običan is Assistant Clinical Professor of Obstetrics and Gynecology at the George Washington University School of Medicine and Health
Sciences. She is a Fellow at the Reproductive Toxicology Center.
Anthony Scialli is Director of the Reproductive Toxicology Center and Senior Scientist at Tetra Tech Sciences.
*Correspondence to: Sarah Običan, M.D., 851 N Glebe Rd Apt 1319, Arlington, VA 22203-4150. E-mail: [email protected]
DOI 10.1002/ajmg.c.30310
Published online in Wiley Online Library (wileyonlinelibrary.com).
ß 2011 Wiley-Liss, Inc.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
TABLE I. Hill Criteria for Causation [Hill, 1965]
Strength of the association (the likelihood that the association is not due to chance, bias,
or confounding)
Consistency of the association (the association is reproduced in different populations)
Speciﬁcity (uniqueness of the association both with respect to the exposure and with
respect to outcome)
Temporal relationship (the putative cause comes before the effect)
Coherence (the association is compatible with related knowledge)
Biologic gradient (there is a dose–response effect)
Biologic plausibility (the association does not violate known principles)
Experiment (reducing the putative cause reduces the effect)
Analogy (evidence is similar to that for other cause–effect relationships)
recommending that women consider
avoiding lithium during early pregnancy
or that they consider fetal echocardiography if they have been exposed to
lithium is appropriate counseling, even
in the absence of certainty that lithium
therapy increases the risk of Ebstein
anomaly.
PHARMACEUTICAL
PRODUCTS
Thalidomide
In 1957, a simple phthalimide derivative
called thalidomide was marketed in
Europe and elsewhere as a sedative/
antiemetic at a dose of 50–150 mg/day.
The drug was to become the most
widely known cause of human birth
defects in the world and one that
changed the way exposures are evaluated
for teratogenic potential. Thalidomide
has little toxicity in adults, making it one
of the few agents that is selectively toxic
to the embryo. At a meeting in 1959, a
German pediatrician presented a girl
with phocomelia, an unusual limb
reduction defect in which the hand or
foot arises close to the shoulder or hip.
An additional two children with similar
ﬁndings were presented in September
1960. By November 1961, 34 congenital long bone malformations were
reported, and William MacBride and
Widukind Lenz independently made
the association between these malformations and thalidomide. Secular trend
analysis shows a clear parallel between
sales of thalidomide and the appearance
of characteristic limb malformations
(Fig. 1).
Thalidomide therapy during pregnancy is associated with limb reduction
defects, facial hemangiomata, esophageal and duodenal atresia, tetralogy of
Fallot, renal agenesis, anomalies of the
external ear, and cranial nerve abnormalities. The sensitive time period for
the production of human thalidomide
limb defects is 21–36 days from conception (Fig. 2). About 20% of pregnancies
exposed during this period result in
children with anomalies.
The most sensitive experimental
animal models for thalidomide embryo
toxicity appear to be the monkey and
rabbit. Although it is often said that
thalidomide is not teratogenic in rats,
oral thalidomide causes resorptions in
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this species and intravenous administration of thalidomide to rats produces
skeletal abnormalities involving the ribs,
vertebra, hips, and tail [Schumacher
et al. 1968a]. The increased sensitivity
of rabbits compared to rats appears due at
least in part to pharmacokinetic differences between the species [Schumacher
et al., 1968b].
In 1998, Thalomid, a brand of
thalidomide, was approved by the US
Food and Drug Administration (FDA)
for the treatment of erythema nodosum
leprosum at a dose of 100–300 mg/day.
FDA subsequently approved thalidomide for the treatment of multiple
myeloma in 2006. Doses for multiple
myeloma start at 200 mg/day. The prescribing and dispensing of thalidomide is
strictly controlled in the US in an effort
to prevent use by women who are
pregnant [Zeldis et al., 1999].
ACE Inhibitors
Angiotensin converting enzyme (ACE)
inhibitors are antihypertensives that
inhibit the conversion of the biologically
inactive angiotensin I to angiotensin II,
a potent vasoconstrictor. During the
second and third trimester of pregnancy,
ACE inhibitors reduce fetal blood pressure and decrease renal function, which
can cause oligohydramnios, intrauterine
growth restriction, renal dysplasia, anuria, renal failure, hypocalvaria, and death
[reviewed by Tabacova et al., 2003].
Figure 1. Sales of thalidomide and the appearance of the typical limb malformations
in Germany. Drawn from data presented by Lenz [1988].
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
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skull hypoplasia, and fetal death with use
of at least some ARBs during pregnancy
[e.g., Saji et al., 2001].
Isotretinoin
Figure 2.
Sensitive periods for thalidomide associated limb defects.
Since 1992, the US Food and Drug
Administration has required a warning
regarding second and third trimester
fetotoxic effects of all ACE inhibitors.
The ﬁrst report of fetal adverse
effects with the use of an ACE inhibitor
was published in 1981. A woman took
captopril in her 26th week of gestation.
Oligohydramnios was noted in the
28th week and a cesarean section was
performed in the 29th week. The child
was anuric and hypotensive and died
a week later. On autopsy, hemorrhagic
foci were found in the renal cortex and
medulla [Guignard et al., 1981].
The most common abnormalities
due to ACE inhibitors are skull hypoplasia and renal dysfunction related to
prolonged exposure rather than a ﬁrst
trimester insult. Fetal renal impairment
can result in anuria and oligohyrdamnios, which can secondarily induce
anomalies such as hypoplastic lungs,
limb contractures, and craniofacial abnormalities [Buttar, 1997]. The hypocalvaria has been attributed to pressure
on the skull from the uterus and
decreased perfusion of the skull from
fetal hypotension. Other reported cases
include patent ductus arteriosus, IUGR
and fetal death. There have been case
reports of a reversal of oligohydramnios
after discontinuation of ACE inhibitor
therapy [e.g., Chisholm et al., 1997].
There is no unanimity on whether
ACE inhibitor therapy during early
pregnancy increases the risk of malformations. ACE inhibitors were reported
to increase heart and central nervous
system malformations after ﬁrst trimester use in a study that used Tennessee
Medicaid records to ascertain exposure
and outcome [Cooper et al., 2006].
These malformations included seven
cardiac septal defects, two patent ductus
arteriosus, one spina biﬁda, one microcephaly, and two eye abnormalities. A
record-linkage study from Finland, published in abstract, identiﬁed an increase
in malformations after ﬁrst trimester
ACE inhibitor therapy, but the increase
was explained by maternal diabetes
mellitus [Malm et al., 2008]. A study
from the Swedish Medical Birth Registry described an association between
antihypertensive medication use during
early pregnancy and cardiovascular
defects in the offspring; however, there
was no difference in the risk estimates for
ACE inhibitors and beta blockers, and
the association for ACE inhibitors was
not statistically signiﬁcant [Lennestål
et al., 2009]. A teratology information
service study from Israel and Italy found
no increase in malformations in the
offspring of 252 women exposed to
ACE inhibitors or angiotensin-receptor
blockers (ARBs) in the ﬁrst trimester
[Diav-Citrin et al., 2011].
ACE inhibitors are unusual in being
considered as a group. Under ordinary
circumstances, teratogenicity is unique
to speciﬁc agents under speciﬁc conditions of exposure. Because ACE
inhibition is considered central to the
ACE inhibitor fetopathy, these drugs are
considered to have similar potential for
fetal harm. The assumption that interference with the renin-angiotensin system is central to the ACE fetopathy has
been applied to ARBs and is supported
by case reports of oligohydramnios, fetal
Retinoids are vitamin A like chemicals
that have an effect on epithelial cell
differentiation. Systemic 13-cis-retinoic
acid (isotreinoin) and topical all-transretinoic acid (tretinoin) are used in the
treatment of severe cystic acne. Isotretinoin (Accutane1) was licensed in the
US in 1982. Isotretionoin produces
malformations of the central nervous
system, limbs, cardiovascular system, and
face in mice, rats, monkeys, and rabbits
[Fantel et al., 1977; Goulding and Pratt,
1986; Nau, 2001]. These malformations
are due at least in part to the inhibition of
migration of cranial neural crest cells
during early embryonic development.
Isotretinoin is less potent in mice
than in humans due to a shorter half-life
and decreased placental transfer. In
addition, rodent maternal metabolism
is through b-glucoronidation and not
metabolism through 4-oxo-isotretinoin
as is in rabbits, monkeys, and humans
[Nau, 2001]. Kochhar and Penner
[1987] speculated that 4-oxo-isotretinoin, which has a longer half-life than
isotretinoin, might be a major contributor to teratogenesis in humans. They
concluded that metabolism in the mother is an important determinant of
embryotoxicity in a given species. Differences in maternal metabolism may be
the reason that the teratogenic dose is
75–150 mg/kg in the mouse, 10 mg/kg
in the rabbit, and 2.5–5 mg/kg in the
human [Nau, 2001]. Another estimate
of the teratogenic dose in humans is as
low as 0.5–1.5 mg/kg/day [Adams and
Lammer, 1993]. Human embryos may
be more sensitive to isotretinoin than
embryos of other species due to slow
elimination of the drug and continuous
isomerization to all-trans–retinoic acid
[Nau, 2001].
The teratogenicity of therapeutic
doses of isotretinoin was predicted based
on experimental animal studies and the
product was so labeled when it was ﬁrst
sold in the US in 1982. Case reports of
malformed children born after maternal
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
isotretinoin therapy appeared in 1984
[De la Cruz et al., 1984; Stern et al.,
1984]. Lammer et al. [1985] published
the ﬁrst systematic description of the
embryopathy in humans. Among 154
The teratogenicity of
therapeutic doses of isotretinoin
was predicted based on
experimental animal studies
and the product was so labeled
when it was ﬁrst sold in the
US in 1982. Case reports of
malformed children born after
maternal isotretinoin therapy
appeared in 1984. Lammer
et al. published the ﬁrst
systematic description of the
embryopathy in humans.
isotretinoin-exposed pregnancies, 95
resulted in elective abortion, 12 in
spontaneous abortion, 21 in infants without malformations, and 26 in infants with
malformations. The relative risk of
malformations was 25.6 (95% conﬁdence interval 11.4–57.5). All malformed infants had a history of exposure
to isotretinoin on or before 28 days of
gestation. The four territories most
consistently affected were cranium/face,
heart, thymus, and central nervous system. Craniofacial abnormalities included
small, low set ears, micrognathia, and ﬂat
depressed nasal bridge. Heart defects
consisted of conotruncal malformations,
and central nervous system abnormalities
included hydrocephalus.
Prenatal exposure to isotretinoin
places a child at risk beyond only the
structural abnormalities. Forty-seven
percent of children exposed to isotretinoin in utero tested in the subnormal
range for intelligence [Adams and
Lammer, 1993]. There is a decrease in
performance of visual-spatial processing
tasks; overall males tend to be affected
more than females [Adams, 2004].
Although prominent product labeling and a restrictive prescribing program
have been in place, for some years,
Bérard et al. [2007] found that the
annual pregnancy incidence rate is
32.7/1,000 in women taking isotretinoin [2007]. In this study, 84% of
women who became pregnant on isotretinoin terminated their pregnancies.
Guidelines recommend discontinuing
the medication 4 weeks prior to pregnancy, although pharmacokinetic considerations demonstrate that the drug is
cleared from the body 10 days after the
last dose.
There have been case reports of
malformations after pregnancy exposure
to topical tretinoin that suggested retinoid embryopathy to the reporting
authors [e.g., Camera and Pregliasco,
1992; Lipson et al., 1993]. However, the
low degree of systemic absorption and
the available controlled studies, which
include just over 400 exposed pregnancies, do not support the conclusion that
topical tretinoin therapy increases the
risk of malformations [Jick et al., 1993;
Shapiro et al., 1997; Loureiro et al.,
2005].
Etretinate and its metabolite acitetin
are avoided during pregnancy due to
case reports of malformations consistent
with retinoid embryopathy associated
with these medications. Etretinate has
the disadvantage of very slow elimination, and there is a case report of an
infant with retinoid-like defects conceived 1 year after discontinuation of
maternal etretinate therapy [Lammer,
1988]. Acitretin is more rapidly excreted, but there is evidence that acitretin
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can be metabolized to etretinate. To our
knowledge, there have been no reports
of retinoid embryopathy in pregnancies
conceived after discontinuation of acitretin therapy.
Methotrexate
Folic acid is a cofactor in the synthesis of
thymidylate, a rate limiting step in DNA
synthesis. Folic acid analogs may interfere with DNA synthesis and have found
use in the treatment of ectopic pregnancy, psoriasis, rheumatoid arthritis,
systemic lupus erythematosus, and some
malignancies. Among the earliest folic
acid analogs were aminopterin and
amethopterin, which is known more
commonly as methotrexate (Fig. 3).
Methotrexate developmental abnormalities have been produced in animal
models including chickens, mice, rats,
and rabbits [Skalko and Gold, 1974;
Schmid, 1984; Zamenhof, 1985;
DeSesso and Goeringer, 1992]. The
most common malformations involve
the central nervous system and palate.
Aminopterin interferes with early
human fetal development, and this
compound was used as an abortifacient
in the 1940s and 1950s. Failed abortion
after aminopterin sometimes resulted in
fetal malformation [Thiersch and Phillips, 1950; Thiersch, 1952]. Subsequent
reports also identiﬁed malformations in
newborns surviving attempted aminopterin abortion [Meltzer, 1956; Warkany
et al., 1959; Shaw and Steinbach, 1968].
In these case reports, the administration
of aminopterin had been between 4 and
12 weeks gestation. The associated
Figure 3. The structure of methotrexate. The arrows show the differences from folic
acid, which consist of an amino group in place of a hydroxyl group and a methyl group in
place of a hydrogen.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
abnormalities included meningoencephalocele, hydrocephalus, anencephaly,
cleft palate, absent parietal bones, incomplete skull ossiﬁcation, and limb
malformations.
Case reports of similar malformations after methotrexate have also
appeared. Feldkamp and Carey [1993]
presented a review of the case reports of
malformations after methotrexate or
aminopterin. They suggested a methotrexate dose of more than 10 mg/week is
necessary to produce anomalies and that
the sensitive period is 6–8 weeks postconception. Defects described as classic
for methotrexate/aminopterin are clover-leaf skull with a large head, sweptback hair, low-set ears, prominent eyes,
and wide nasal bridge.
The prevalence of malformations
after methotrexate therapy during pregnancy is not known. Of particular
interest is the prevalence of malformations after use methotrexate to terminate
suspected ectopic pregnancy when an
intrauterine pregnancy continues after
therapy. There are case reports of
malformations in surviving children
[Adam et al., 2003; Chapa et al., 2003;
Usta et al., 2007]. Some practitioners
recommend folinic acid supplementation for women who continue their
pregnancies after treatment with methotrexate and ultrasound examination to
evaluate fetal anatomy.
It is not clear how long conception
should be delayed after successful treatment of ectopic pregnancy with methotrexate, inasmuch as the drug may persist
in the liver for months. There is a
study showing no difference in outcome
in pregnancies conceived less than
6 months compared to more than
6 months after methotrexate therapy;
however, there were only 45 pregnancies
in the less-than-6-month group [Svirsky
et al., 2009].
rodenticide, warfarin was adopted for
use in clinical medicine. Advantages of
warfarin were water solubility, oral
bioavailability, and reversibility by the
administration of vitamin K. A case
report by Disaia [1966] presented a
pregnancy exposed to warfarin therapy
for a prosthetic heart valve. The infant
was born with hypoplastic nose, optic
atrophy, and mental retardation.
Two years later, Kerber et al. [1968]
proposed a relationship between vitamin
K antagonist ingestion and characteristic
fetal anomalies. Shaul and Hall [1977]
reviewed the literature and reported on
14 mothers who ingested oral anticoagulants during pregnancy. All 14
children were born with a hypoplastic
nose; many of them had stippled epiphyses and ﬁve had eye abnormalities.
Warfarin embryotoxicity is most
likely between 6 and 9 weeks of gestation
[Hall et al., 1980; Iturbe-Alessio et al.,
1986], although Schaefer et al. [2006]
did not see warfarin-related effects with
exposures prior to 8 weeks gestation.
Warfarin
In 1948, a potent, naturally occurring
coumarin called warfarin was marketed
as a rodenticide, killing rats and mice
by inducing internal hemorrhage
[reviewed by Wardrop and Keeling,
2008]. Soon after its success as a
Warfarin embryotoxicity is
most likely between 6 and
9 weeks of gestation, although
Schaefer et al. did not see
warfarin-related effects
with exposures prior to
8 weeks gestation.
Warfarin therapy during pregnancy has
been associated with spontaneous abortion, stillbirth, nasal hypoplasia, stippled
epiphyses, distal limb hypoplasia, and
malformations of the central nervous
system, eye, jaw, and urinary tract
[Harrod and Sherrod, 1981; Oakley,
1983; Hall, 1989; Pauli and Haun,
1993; Schaefer et al., 2006]. The use of
oral anticoagulants throughout pregnancy is associated with warfarin embryopathy in 6.4% (95% conﬁdence
interval, 4.6–8.9%) of livebirths [Chan
et al., 2000]. Substituting heparin for
warfarin between 6 and 12 weeks of
gestation eliminated the risk of warfarin
5
embryopathy, but it did not eliminate the
risk of spontaneous abortions or stillbirths [Chan et al., 2000]. The poorest
pregnancy outcomes were associated
with a daily warfarin dose of more than
5 mg [Cotrufo et al., 2002].
After the ﬁrst trimester, the fetus
continues to be at risk for CNS defects
likely caused by microhemorrhages in
neuronal tissue due to low stores of
vitamin K and low levels of vitamin K
dependent procoagulant factors in the
fetus, and neurological abnormalities in
children and adults born to women who
use warfarin during pregnancy have
been reported [Hall et al., 1980; Cotrufo
et al., 2002; Raghav and Reutens, 2007].
A rat model of the nasal hypoplasia
and skeletal dysplasia of warfarin embryopathy was developed by treating rats
postnatally with warfarin and using
supplemental vitamin K1 to permit
survival [Howe and Webster, 1992].
Extrahepatic vitamin K deﬁciency in
this model was responsible for the
induced abnormalities.
Phenytoin
Phenytoin is most commonly used as an
antiepileptic medication. It suppresses
abnormal brain activity by stabilizing
voltage-gated sodium channels. Phenytoin is a treatment option in trigeminal
neuralgia and some cardiac antiarrhythmias.
Exposure during pregnancy has
been associated with a constellation of
abnormalities sometimes called the fetal
hydantoin syndrome (Table II). The
prevalence of major malformations
among the offspring of women taking
phenytoin during pregnancy is about
10% [Meador et al., 2006]; minor malformations occur considerably more
commonly. Polytherapy with anti-epileptic drugs is associated with a higher
likelihood of fetal adverse effects than is
monotherapy [Samren et al., 1999].
Use of phenytoin during pregnancy has
been associated by case reports with a
neuroectodermal tumors, speciﬁcally
neuroblastomas, in the offspring
[Satgé et al., 1998]. Without controlled
studies, this association remains tentative
at best.
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Carbamazepine
TABLE II. Features of the Fetal
Hydantoin Syndrome
Short nose
Low or broad nasal bridge
Epicanthic folds
Hypertelorism
Microcephaly
Abnormal ears
Wide mouth
Oral clefts
Hypoplasia of distal phalanges
Fingerlike thumbs
Short/webbed neck
Low hairline
Abnormal mental development
Abnormal motor development
The ﬁrst association between phenytoin and malformations is credited
to Janz and Fuchs [1964], but these
investigators were focused on anticonvulsant therapy in general, not phenytoin. Janz and Fuchs polled women with
epilepsy about malformations in their
children and came up with a prevalence
of 2.2% [reviewed by Kalter, 2003].
The term fetal hydantoin syndrome
was coined by Hanson and Smith
[1975], who described ﬁve children
whose mothers received hydantoin
anticonvulsants. The children were
described as having ‘‘craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deﬁciency, and mental
deﬁciency.’’
There has been and remains a
question of whether malformations
associated with phenytoin are due to
the medication itself, maternal epilepsy,
or an underlying genetic disorder that
gives rise to maternal epilepsy and fetal
malformations. At present, most people
favor a direct effect of the medication on
embryo development, particularly due
to the experimental animal support for a
direct effect [reviewed by Finnell and
Dansky, 1991]. One theory holds that
sensitivity to phenytoin embryopathy is
conferred by a decreased ability to
detoxify an arene oxide intermediate of
the drug [Buehler et al. 1990]. This
detoxiﬁcation ability is genetically determined and would be evidence of a
gene-environment interaction.
Carbamazepine is an anticonvulsant
drug used in treatment of bipolar
disorder and trigeminal neuralgia. As is
the case for phenytoin, Janz and Fuchs
[1964] are credited with the ﬁrst investigation of the possibility of teratogenicity with the use of antiepileptic drugs.
Niebyl et al. [1979] reviewed the
literature including 94 infants with some
exposed to carbamazepine alone or in
combination with other anticonvulsant
drugs and suggested no evidence of
teratogenicity. Indeed, for some years,
carbamazepine was considered by many
clinicians to be the anticonvulsant of
choice in pregnancy.
The identiﬁcation of the adverse
developmental effects of carbamazepine
therapy can be credited to Jones et al.
[1989], who described a malformation
syndrome in eight exposed children and
conﬁrmed in a prospective series that the
syndrome occurred more often than
expected by chance. They reported
craniofacial defects in 11%, ﬁngernail
hypoplasia in 26%, and developmental
delay in 20% of children from 35
prospectively enrolled pregnancies. The
authors noted the similarity of these
outcomes to the fetal hydantoin syndrome and proposed a common mechanism. The developmental delay noted by
these and later authors has been questioned due to lack of adjustment for
parental cognitive testing.
Two years after this report, the
FDA’s Franz Rosa [1991] published a
communication based on his Michigan
Medicaid data base in which maternal
prescriptions were linked to subsequent
insurance claims for malformation-related services in the offspring. Rosa
proposed based on four children with
spina biﬁda and a review of other reports
that carbamazepine causes spina biﬁda in
1% of exposed pregnancies. Although
this estimate has not been rigorously
conﬁrmed, the 1% ﬁgure remains
enshrined in counseling practice. High
doses of folic acid are often prescribed to
pregnant women on carbamazepine in
spite of the lack of evidence of beneﬁt of
doses above those usually recommended
in pregnancy.
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A study from the Hungarian Case–
Control Surveillance of Congenital
Abnormalities identiﬁed an association
between carbamazepine exposure during pregnancy and posterior cleft palate
(odds ratio 13.7, 95% conﬁdence interval 3.9–47.5) [Puhó et al., 2007]. This
surveillance project did not include
adequate information on possibly confounding exposures to nicotine and
ethanol.
Carbamazepine exposed infants
have about a twofold greater risk of
malformations than the general population with major malformation rates of
about 2% [Diav-Citrin et al., 2001;
Morrow et al., 2006], although some
estimates of adverse neonatal outcome
are up to 8% [Meador et al., 2006; Eroğlu
et al., 2008]. A relationship between
carbamazepine dose and malformation
prevalence has been found, with a
twofold increase in malformations in
the offspring of women on daily
doses of >1,000 compared to <400 mg
[Morrow et al., 2006]. There appears to
be a higher rate of malformation with
carbamazepine in polytherapy compared to monotherapy.
Valproic Acid
Valproic acid is used as an anticonvulsant
and in the treatment of bipolar disorder
and migraine. Experimental animal
studies have demonstrated an increase
in malformations in multiple species
[Binkerd et al., 1988; Hendrickx et al.,
1988; Narotsky et al., 1994]. Indeed, it
was based on experimental animal
studies that the teratogenicity of valproic
acid therapy was ﬁrst considered. Brown
et al. [1980] had noted that valproic acid
therapy in pregnant mice produced
exencephaly in the offspring at dose
levels that were low compared to dose
levels at which maternal toxicity was
evident. They posed the question in a
letter-to-the-editor of The Lancet as to
whether there was clinical evidence of
teratogenicity. In response, a group of
clinicians wrote that they had treated 12
women during pregnancy with valproic
acid, often in combination with phenytoin, and all the children were normal
[Hiilesma et al., 1980].
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
It was not until 2 years later that, in
an unrelated epidemiology study, valproic acid was associated with a 20-fold
increase in lumbar meningomyelocele in
human pregnancy [Bjerkedal et al.,
1982; Robert and Guibaud, 1982].
Other abnormalities have been reported
in the offspring of women being treated
with valproic acid including atrial septal
defect, cleft palate, hypospadias, craniosynostosis, radial aplasia, and developmental delay [Verloes et al., 1990; Ylagan
and Budorick, 1992; Wyszynski et al.,
2005; Jentink et al., 2010].
Large studies have produced estimates of the incidence of congenital
malformations in children exposed to
valproic acid during pregnancy ranging
from 6 to nearly 18%. The prospective
observational
Neurodevelopmental
Effects of Antiepileptic Drugs Study
reported a birth defect rate of 17.7%
among 69 babies with ﬁrst trimester
valproic acid exposure [Meador et al.,
2006]. The frequency of major congenital anomalies in children exposed to
valproate monotherapy was 9% in
pooled data from ﬁve prospective European studies with an apparently higher
incidence of malformations in children
exposed to valproate plus other anticonvulsants [Samrén et al., 1997]. The
Antiepileptic Drug Pregnancy Registry
maintained at Massachusetts General
Hospital reported 16 malformed children among 149 pregnancies (incidence
10.7%) exposed to monotherapy with
valproic acid [Wyszynski et al., 2005].
The UK Epilepsy and Pregnancy Register reported 44 children with major
malformations among 715 pregnancies
exposed to valproate monotherapy, for
an incidence of 6.2% [Morrow et al.,
2006]. The Australian Pregnancy Registry identiﬁed 19 malformed children
among 113 pregnancies exposed to
valproic acid, giving an incidence of
16.8% [Vajda et al., 2006].
Higher dose levels of valproic acid
therapy appear to be associated with a
greater likelihood of teratogenicity, and
1,000 mg/day has been suggested as a
threshold for adverse effects on morphological development. This dose level
was also suggested as threshold for
adverse effects of valproic acid therapy
on offspring cognitive function [Meador
et al., 2009]. Mean IQ scores in children
exposed to higher dose levels were 6–9
points lower than those of children
exposed to other anticonvulsants or to
lower dose levels of valproic acid.
Other Anticonvulsants
There is some question about whether
other anticonvulsant medications increase the risk of congenital malformations. Part of the uncertainty is based on
the possibility that seizure disorders
themselves impose an increased risk of
abnormal development, although current thought has minimized this possibility. Much of the difﬁculty in studying
the older anticonvulsant medications has
been the frequent use of combination
therapy. For example, there has been
suspicion that phenobarbital therapy
during pregnancy can increase the risk
of malformations, but most use of
phenobarbital for epilepsy was traditionally in combination with phenytoin.
There have been case reports, however,
of phenytoin-like malformations in
children exposed during gestation only
to phenobarbital, and a controlled study
suggested that the prevalence of malformations with phenobarbital monotherapy was similar to that with other
anticonvulsant monotherapy [Bertollini
et al., 1987]. Current counseling practice identiﬁes phenobarbital therapy as
being associated with an increased risk of
congenital malformations similar to
those associated with phenytoin.
The newer anticonvulsant medications have been evaluated in various
pregnancy registries with evidence of an
increase in malformations for lamotrigine and topiramate. With respect to
lamotrigine, some registries have not
shown an increase in risk, but the
antiepileptic drug registry at the Massachusetts General Hospital reported
about a 10-fold increase in all nonsyndromic orofacial clefts and a 21-fold
increase in isolated cleft palate [Holmes
et al., 2008]. The comparator group for
these estimates was based on historical
experience in the hospital. For topiramate, increases in malformations and
low birth weight have been suggested by
7
two registries [Vajda et al., 2007; Herndández-Dı́az et al., 2010]. In one of the
registries, cleft lip appeared to be overrepresented among the malformations.
The Massachusetts General registry
continues to monitor the outcome of
pregnancies in which anticonvulsant
medications have been used. To learn
more about this registry or to enroll
subjects, call 1-888-233-2334, or visit
online, http://www.massgeneral.org/
aed. Outside North America, the International Registry of Antiepileptic Drugs
and Pregnancy can be reached at http://
www.eurapinternational.org.
Penicillamine
Penicillamine is a heavy metal chelating
agent used to treat Wilson disease,
rheumatoid arthritis, and cystinuria.
Penicillamine has also been used to
chelate mercury, cadmium, and lead.
Chelation of copper or zinc has been
proposed as a mechanism by which
penicillamine may interfere with normal
embryo development, particularly with
respect to connective tissue.
Penicillamine given in high doses to
pregnant rats and mice has been associated with increases in connective tissue,
skeletal, palate, and lung abnormalities in
the offspring [Steffek et al., 1972; Merker
et al., 1975; Irino et al., 1982; Keen et al.,
1982, 1983; Kilbourn and Hess, 1982;
Mark-Savage et al., 1983; Myint, 1984;
Dubick et al., 1985]. In some of these
studies, copper supplementation reduced
the teratogenic effects of penicillamine.
A case report of an infant with lax
skin, hyperﬂexibility of the joints, and
poor wound healing born to a mother
who had received high-dose penicillamine (2,000 mg/day) for cystinuria
appeared in 1971 [Mjolnerod et al.,
1971]. Other children with lax skin,
inguinal hernias, and other connective
tissue problems have been reported after
therapy during pregnancy with penicillamine in doses from 900 to 1,500 mg/
day [Solomon et al., 1977; Linares et al.,
1979; Harpey et al., 1983; Rosa, 1986].
It is possible that fetal connective
tissue abnormalities are related to abnormally low maternal or fetal tissue levels
of copper or zinc. The offspring of
8
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
women with Wilson disease may not be
at risk if maternal copper levels are
reduced only to normal. This theory
would predict that women treated with
high doses of penicillamine and women
treated for illnesses other than Wilson
disease would be at particular high risk of
giving birth to an affected child. There
are, however, case reports that do not ﬁt
with this theory, including a normal
infant born after maternal treatment
with penicillamine 2,250 mg/day for
cystinuria [Laver and Fairley, 1971] and
an abnormal infant born to a woman
treated for Wilson disease with penicillamine 900 mg/day [Solomon et al., 1977].
Abnormalities associated with
pregnancy exposure to penicillamine
appear to occur infrequently. Endres
[1981] summarized the outcome of 87
pregnancies exposed to penicillamine,
46 of which were exposed throughout
pregnancy. There were two children
with connective tissue abnormalities.
The lax skin reported in affected children may resolve with age [Linares et al.,
1979]. It has been suggested that the use
by pregnant women with Wilson disease
of low doses (250 or 500 mg/day) of
penicillamine might offer protection
from penicillamine-associated birth
defects while permitting adequate control of the underlying illness [Marecek
and Graf, 1976]. This proposal was based
on eight cases under the authors’ care
and has not been subjected to rigorous
conﬁrmation.
Misoprostol
Misoprostol is a synthetic prostaglandin
E1 analogue that is used for the prevention of gastric ulcers associated with
nonsteroidal anti-inﬂammatory drugs,
to empty the uterus in incomplete
miscarriage and early voluntary abortion, to ripen the cervix in preparation
for labor, and in the treatment of
postpartum hemorrhage.
Use of misoprostol as an abortifacient fails in 10% of cases [Song, 2000].
This risk of failure may be particularly
high when misoprostol is used as a single
agent instead of in combination with
mifepristone or methotrexate [Golderg
et al., 2001]. The risk of misoprostol
exposure of early pregnancies is highest
in countries where abortion is illegal or
not widely available. In Brazil, for
example, the use of misoprostol is not
monitored by health professionals and
frequently results in the birth of children
after exposure to misoprostol in the ﬁrst
trimester [Philip et al., 2002].
In 1991, the ﬁrst cases of fetal
anomalies associated with use of misoprostol were reported from Brazil [Fonesca
et al., 1991; Schonhofer, 1991]. Fonesca
et al. [1991] described the association of
skull malformations with the use of 400–
600 mg misoprostol in the ﬁrst trimester of
pregnancy. The infants described were
born with frontal and/or temporal defect
of the cranium, exposing the dura matter
and the underlying cerebrum.
In one series, the most common
anomalies associated with use of misoprostol in pregnancy involved the lower
limbs and included clubfoot, meromelia,
and joint constriction [Philip et al.,
2002]. There were also anomalies of
cranial nerves III–XII with the majority
of anomalies associated with cranial
nerve VI, followed by V and XII. Many
of the cranial nerve anomalies resembled
the Möbius syndrome, with loss of
cranial motor nerve function resulting
in facial bilateral paralysis.
Another series of 42 infants born
with congenital anomalies after exposure to misoprostol during gestation
reported that the most common dose
of misoprostol used was 800 mg with a
range of 200–16,000 mg and that all
exposures were in the ﬁrst trimester
[Gonzalez et al., 1998]. The most
common anomalies were clubfoot with
abnormalities of cranial nerves V–VII.
Other anomalies included arthrogryposis, terminal transverse limb defects, and
constriction bands.
The proposed mechanism of these
anomalies is interruption of normal
vascular development [Bavnick and
Weaver, 1986; Vargas et al., 2000].
Most misoprostol exposures in pregnancy occur between 5 and 8 weeks after the
last menstrual period [Gonzalez et al.,
1998; Philip et al., 2002], a sensitive time
for limb development.
A review of four studies comprising
4,899 cases of congenital anomalies com-
ARTICLE
pared to 5,742 normal controls evaluated
the risk of fetal malformations in relation
to misoprostol exposure [da Silva Dal
Pizzol et al., 2006]. Increased risks related
to misoprostol use were found for Möbius
syndrome (OR 25.31, 95% conﬁdence
interval 11.11–57.66) and terminal transverse limb defects (OR 11.86, 95%
conﬁdence interval 4.86–28.90).
Among offspring of 120 women
who used misoprostol in an attempt to
induce abortion, an association was
found between misoprostol use and total
congenital anomalies (OR ¼ 2.64;
95%CI: 1.03–6.75) [da Silva Dal Pizzol
et al., 2008]. The anomalies identiﬁed in
this study included meningomyelocele,
microcephaly, clubfoot, syndactyly, and
ﬁngernail defects. The reported incidence of all anomalies in misoprostolexposed fetuses was 4.24%. Infants were
evaluated only after delivery, leading to
possible under-reporting of Möbius
syndrome and other central nervous
system abnormalities, which may not
be apparent until months later.
Diethylstilbestrol
Diethylstilbestrol (DES) is a synthetic
nonsteroidal estrogen. This compound
was used as a pharmaceutical from
around 1938 until 1971 in the US and
in Europe until 1978 in an attempt to
prevent miscarriage, premature delivery,
and other pregnancy complications.
Doses varied but typically started at
5 mg/day early in pregnancy with a
steady increase to 150 mg/day at term.
In 1971, Herbst et al. reported eight
cases of vaginal adenocarcinoma in young
women [Herbst et al., 1971]. The authors
had seen seven of the patients, aged 15–
22 years, at the Vincent Memorial
Hospital in Boston between 1966 and
1969. Vaginal carcinoma is very rare in
women in this age group, and vaginal
carcinoma in any age group is virtually
always squamous, not glandular, so seeing
this many cases of vaginal adenocarcinoma in a short period of time raised the
suspicion that a new causal factor was at
play. The authors performed a casecontrol study, comparing historical
aspects of the pregnancies of the eight
patients they had identiﬁed with 32
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
controls matched for date of birth (within
5 days) and hospital service (ward or
private). They found that seven of the
eight patients had been exposed during
pregnancy to diethylstilbestrol given for a
maternal history of miscarriage and/or
bleeding in the current pregnancy. None
of the control patients had been exposed
to diethylstilbestrol.
This ﬁrst paper was remarkable in
being not only the ﬁrst case series but also
the ﬁrst controlled study of the association. Moreover, the authors offered the
theory in this ﬁrst paper, a theory that is
still in vogue, that the adenocarcinoma
was due to adenosis (the presence of
glandular elements in the vaginal epithelium) in the diethylstilbestrol-exposed
vagina that was at risk for malignant
transformation. Subsequent work by
Herbst and coworkers led to an estimate
that 1 in 1,000 women with intrauterine
exposure to diethylstilbestrol would develop adenocarcinoma and that about
two-thirds of women who developed
adenocarcinoma would have a history of
maternal treatment during pregnancy
with diethylstilbesterol or another estrogen [Melnick et al., 1987].
Diethylstilbestrol exposure during
pregnancy also results in abnormalities of
the uterus in more than two-thirds of
female offspring; these abnormalities
including hypoplasia and irregularity of
the cavity, a T-shaped cavity, and constriction bands [reviewed by Goldberg
and Falcone, 1999]. The uterine abnormalities are associated with infertility
and preterm delivery. Abnormalities of
the cervix include collars, hoods, and
septae. The risk of female genital tract
abnormalities is highest with exposure
prior to 15 weeks gestation (44%),
intermediate at 15–22 weeks (22%),
and lowest after 23 weeks gestation (5%)
[Jefferies et al., 1984]. Male offspring
have been found to have an increased
risk of cryptorchidism, epididymal cyst,
and orchitis, with stronger associations
when exposure is before 11 weeks
gestation [Palmer et al., 2009].
defect called Ebstein anomaly, in which
the tricuspid valve is displaced into
the right ventricle, but the evidence
is contradictory. The ﬁrst connection
between lithium therapy and Ebstein
anomaly was published by Nora et al.
[1974]. These investigators obtained
teratology-oriented histories from 733
women. Two women in the group had
taken lithium during pregnancy and both
gave birth to children with Ebstein anomaly.
Based on suspicions raised by experimental animal studies, a Register of
Lithium Babies was started in Denmark
in 1969 and was soon expanded to
include input from Canada, the US,
and elsewhere. An early report from this
registry indicated that there were nine
malformed infants among 118 exposed
pregnancies [Schou et al., 1973]. The
authors cautioned that due to the
retrospective nature of the reporting,
the registry might over-represent abnormal pregnancy outcomes. Not long
thereafter, a publication from this registry reported an analysis based on 143
pregnancies in the registry [Weinstein
and Goldﬁeld, 1975]. There were four
instances of Ebstein anomaly. The
authors concluded that the proportion
of malformations that was cardiac and
the proportion of cardiac malformations
that was Ebstein anomaly exceeded what
would be expected based on general
population rates. The registry would
go on to add an additional two cases of
Ebstein anomaly (from 225 exposed
pregnancies) before it closed in 1979.
The question remained, however,
whether the publicity generated by the
registry served to attract serious defects
in general and Ebstein anomaly cases
in particular. A multicenter teratology
information service study followed
138 pregnancies that included ﬁrst
trimester exposure to lithium [Jacobson
et al., 1992]. There was no increase in
birth defects as a group; however, one
case of Ebstein anomaly was found
among the exposed fetuses based
on antenatal fetal echocardiography.
Lithium
Lithium therapy is often considered to
increase the risk of an unusual cardiac
A multicenter teratology
information service study
9
followed 138 pregnancies that
included ﬁrst trimester exposure
to lithium. There was no
increase in birth defects as a
group; however, one case of
Ebstein anomaly was found
among the exposed fetuses
based on antenatal fetal
echocardiography.
Other observations suggested that lithium exposure may not be an important
causal factor in Ebstein anomaly. A short
communication presented 25 Swedish
and 15 French cases of Ebstein anomaly
with no maternal history of lithium use
during pregnancy [Källén, 1988]. A
case–control study from the Birth
Defects Monitoring Program did not
identify any maternal lithium exposure
during pregnancy for 34 children with
conﬁrmed Ebstein anomaly [Edmonds
and Oakley, 1990]. A Canadian case–
control study of Ebstein anomaly also
found no cases in which there was
maternal exposure to lithium during
pregnancy [Zalzstein et al., 1990]. Based
on the sample size, it was suggested that
the upper limit for any increase in risk
would be 28-fold, or about 0.14%.
The interpretation of the cases from
the Register of Lithium Babies was based
in part on the presumed prevalence of
Ebstein anomaly of 1 in 20,000 births.
More recent reports suggest that Ebstein
anomaly can go undiagnosed until
adulthood and may be associated with
few symptoms [Rosas et al., 2000].
Inasmuch as most lithium-exposed
fetuses and infants now are recommended to undergo echocardiography,
ascertainment of Ebstein anomaly and
other cardiac defects can be expected to
be virtually complete in these pregnancies while unexposed children with
Ebstein anomaly may go undiagnosed
until adulthood. This propensity to
diagnose heart defects in lithiumexposed fetuses and newborns may
contribute to the impression that there
is a causal relationship between the use of
10
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
lithium during pregnancy and cardiac
defects in the offspring.
It is ironic that the experimental
animal studies, which started the suspicions about lithium during pregnancy
almost 50 years ago, can now be cited as
reasons to doubt a causal connection
with cardiac anomalies. Lithium exposure of pregnant laboratory mice and rats
increases malformations only with very
high exposure levels, often given intraperitoneally [Szabo, 1970; Wright et al.,
1971; Smithberg and Dixit, 1982; Marathe and Thomas, 1986; Jurand, 1988].
Other studies in rodents, rabbits, and six
monkeys have failed to show an increase
in malformations with lithium exposure
during pregnancy [Johansen, 1971;
Gralla and McIlhenny, 1972; Hoberman
et al., 1990]. The report by Gralla and
McIlhenny [1972] is brief but conﬁrms
that pregnant animals attained serum
lithium concentrations within or above
the human therapeutic range. The study
by Hoberman et al. [1990] was a standard
developmental study reported from an
experienced laboratory. No experimental animal study, even using extreme
treatment conditions, has shown an
increase in cardiovascular malformations.
Current
counseling
practice
includes the advice that there may be
an increase in Ebstein anomaly after
exposure to lithium. Exposed women
are routinely offered fetal echocardiography. If there is a risk of Ebstein anomaly
associated with lithium, it appears to be
well under 1%. Counselors can advise
their clients that the chance of identifying a cardiovascular anomaly using fetal
or neonatal echocardiography is greater
than the likelihood that any identiﬁed
abnormality is due to lithium. After
counseling, women who elect to continue lithium therapy during their pregnancies should be supported in their
decisions. Hypotonia, kidney, or thyroid
impairment can occur in exposed
neonates, and consideration can be
given during counseling to the nonmalforming effects of this medication.
Methimazole
Methimazole is an antithyroid agent that
has a reputation for causing a punched
out lesion of the scalp called aplasia cutis.
The ﬁrst report of this association
appeared in 1972 [Milham and Elledge,
1972]. This letter-to-the-editor of Teratology read in part, ‘‘In the 6-month
period October 1970–March 1971, 11
cases of newborn scalp defects were
ascertained in Washington State by
birth-certiﬁcate report and physician
questionnaire. The lesions were single,
circular, punched-out, ulcerlike midline
defects of the scalp at the vertex or in the
occipital area. Query of the mothers
revealed that two of the 11 had taken
methimazole. . . during pregnancy for
hyperthyroidism. A third mother had
taken thyroid hormone during her
pregnancy for treatment of hypothyroidism.’’ These authors suggested that
the defect might be associated with
antithyroid drugs or other factors associated with thyroid dysfunction.
In 1985, one of the original authors
published a report of nine cases of scalp
defect, including those he had previously published, associated with maternal
therapy with methimazole or carbimazole, which is metabolized to methimazole [Milham, 1985]. There followed
other case reports of congenital anomalies in children born to women on
methimazole therapy [reviewed by
Diav-Citrin and Ornoy, 2002]. Among
the malformations, choanal and gastrointestinal atresias were given particular
prominence by report authors.
Controlled studies, however, have
mostly failed to conﬁrm that children
with intrauterine exposure to methimazole have an increased risk of aplasia cutis
or other malformations [Momotani
et al., 1984; Van Dijke et al., 1987;
Wing et al., 1994; Di Gianantonio et al.,
2001]. One of these papers equivocated
in their conclusions, because they found
one infant with choanal atresia and
a second infant with esophageal atresia
among 241 pregnancy outcomes after
maternal exposure to methimazole or
carbimazole [Di Gianantonio et al.,
2001].
The exceptional controlled study
was a case-control study of choanal
atresia that identiﬁed a statistically signiﬁcant association with methimazole
therapy with an odds ratio of 17.75, 95%
ARTICLE
conﬁdence interval 3.49–121.40, based
on 10 exposed cases [Barbero et al.,
2008]. These authors postulated that the
association with choanal atresia was due
to the underlying maternal hyperthyroidism rather than to methiazole therapy. They based this conclusion in part on
the study of Momotani et al. [1984],
which found an increase in malformations associated with untreated maternal
hyperthyroidism, and in part on their
belief that the genesis of choanal atresia is
shortly after 9–10 embryonic weeks of
development. This timing would call
into question some of the case reports in
the literature as well as at least one of
their cases, in which exposure did not
occur until 7 months of pregnancy.
Barbero et al. further suggested that the
lack of reports of choanal atresia with
propylthiouracil therapy might be due to
the greater effectiveness of propythiouracil in protecting the embryo from
exposure to excess triiodothyronine.
The prevailing wisdom until recently had been to recommend propylthiouracil for hyperthyroid pregnant
women due in part to the presumption
that therapy with this drug had less
teratogenic liability that methimazole
therapy. Reports of severe and even fatal
hepatic dysfunction associated with
propylthiouracil therapy have resulted
in reconsideration of treatment during
pregnancy. One commentary pointed
out that the incidence of aplasia cutis in
children exposed antenatally to methimazole (0.03%) has never been shown to
be greater than that in the general
population and that choanal atresia may
be associated with the maternal disease
rather than the treatment [Cooper and
Rivkees, 2009]. These authors suggested
that given the uncertainty about malformations with methimazole, it would be
reasonable to treat hyperthyroid women
with propylthiouracil during the ﬁrst
trimester and then to switch the methimazole to decrease the likelihood of
maternal hepatic failure.
Mycophenolate
Mycophenolate mofetil and mycophenolate sodium are used in immunosuppression regimens. Mycophenolate
ARTICLE
therapy was suspected of being teratogenic based entirely on case reports.
There are now controlled studies that
support the teratogenicity of this therapy, although not with unanimity.
The mycophenolate story hit the
streets in 2006 with a paper from
the National Transplant Pregnancy
Registry that reported on 26 mycophenolate-exposed pregnancies born to
18 women [Sifontis et al., 2006].
There were 15 1ive born children of
whom four had malformations. One
child had hypoplastic nails and
shortened ﬁfth ﬁngers. The other three
malformed children had microtia, and
two of these children also had cleft lip
and palate.
Following that report, several case
reports and case series appeared describing mycophenolate-exposed pregnancies resulting in a variety of different
abnormalities (Table III). It is not clear
that this entire array of abnormalities
constitutes a mycophenolate embryopathy. The abnormalities that appear to be
the most characteristic of effects of this
drug are ear abnormalities, facial clefts,
and perhaps conotruncal heart defects
[Carey et al., 2009].
Denominator-based reports do not
give a clear picture of the presence of a
mycophenolate embryopathy or its
prevalence. Adverse event reports summarized in the product labeling indicates
that of 77 pregnancies reportedly exposed to mycophenolate, 25 spontaneously aborted, and 14 resulted in a
malformed infant or fetus. Six of the 14
malformed offspring had ear abnormalities. As the labeling points out, spontaneous adverse event reporting does not
give reliable prevalence rates, because
adverse outcomes may be disproportionately reported compared to normal
outcomes. An abstract from the European Network of Teratology Information
Services reported that malformations
occurred in 8 of 50 prospectively
ascertained pregnancies after mycophenolate exposure, and that the miscarriage
rate (excluding voluntary abortions)
was 35% [Hoeltzenbein et al., 2010].
The malformations included microtia,
tracheoesophageal ﬁstula, hydronephrosis, and atrial septal defect.
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
TABLE III. Malformations From Case Reports of Pregnancy Exposures to
Mycophenolate During Pregnancy
Ear malformations
Microtia
Atretic or absent external auditory canals
Anotia
Absent internal auditory structures
Preauricular pit
Conductive hearing loss
Low set ears
Ocular malformations
Hypertelorism
Coloboma
Microphthalmia
Cataracts
Orofacial malformations
Cleft lip and/or palate
Micrognathia
Nasal biﬁd anomaly or other dysplasia
Central incisor
Cardiovascular malformations
Ventricular septal defect
Atrial septal defect
Anterior aorta
Double-outlet right ventricle
Pulmonary valve stenonosis
Anterior aorta and interventricular communication
Digit anomalies
Hypoplastic nails
Shortened ﬁfth ﬁnger
Polydactyly
Thumb anomalies
Overlapping ﬁngers
Urogenital malformations
Pelvic ectopic kidney
Kidney asymmetry
Hydronephrosis
Tethered foreskin
Bilateral inguinal hernia
Gastrointestinal malformations
Intestinal malrotation
Tracheo-estophageal ﬁstula or atresia
Brain, spine and skeletal abnormalities
Agenesis of the corpus callosum
Immature white matter with focal necrosis
Trigonocephaly
Hydrocephaly
Sacral dimple
Vertebral body anomalies
Rib fusion
Other diagnoses
Polyhydramnios
Intrauterine growth restriction
Umbilical hernia
Short webbed neck, facial coarseness
Non-immune hydrops
Diaphragmatic hernia
From REPROTOX [2011].
11
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
On the other hand, an Iranian
report on 61 pregnancies in 53 renaltransplant patients reported no difference in outcome between pregnancies
exposed to mycophenolate and pregnancies exposed to azathioprine [Ghafari and Sanadgol, 2008]. There are few
details in the paper, but of the 53
women, 38 were exposed to mycophenolate, cyclosporine A, and prednisone
and the other 15 were exposed to
the same regimen with azathioprine
in place of mycophenolate. There
were two infants with malformations,
including clubfoot and hemangioma
(exposure not speciﬁed). A group of
North American teratology information services reported outcomes of
10 pregnancies exposed to mycophenolate; there were four miscarriages, one
voluntary abortion, and ﬁve normal
births [Klieger-Grossmann et al., 2010].
Experimental animal studies do not
support the putative malformation syndrome of ear abnormalities and facial
clefts. These studies, unpublished but
summarized in FDA documents,
showed malformations in rats and rabbits
at exposure levels that did not produce
maternal toxicity. The malformations
consisted of agnathia, anophthalmia, and
hydrocephaly in rats, and failure of
closure of the thoracic wall, renal
agenesis or ectopia, and umbilical and
diaphragmatic hernia in rabbits. Although rare human case reports included
agnathia and diaphragmatic hernia, the
animal models do not show what has
been described in humans as the mycophenolate embryopathy.
Until more detailed denominatorbased data are available, it is not possible
to counsel on the rate at which a
mycophenolate embryopathy occurs.
It appears prudent all the same to
avoid pregnancy exposures to this medication.
RECREATIONAL DRUGS
Ethanol
Ethanol is one of the oldest recreational
drugs. The reputation of ethanol abuse as
a teratogenic exposure likely dates to
ancient Greece, where drinking was
prohibited on the eve of a wedding for
fear of conceiving a damaged child
[Haggard and Jellinek, cited by Streissguth, 1978]. In 1899, Sullivan published
a study of alcoholic women who were
inmates in a Liverpool jail. He reported
an increase in both morbidity and
mortality in infants of those alcoholic
women [cited by Streissguth, 1978].
The ﬁrst report of what is now
known as fetal alcohol syndrome was
published by Lemoine, a French physician, and his coworkers in 1968
[Lemoine et al., 1968; translated and
reprinted as Lemoine et al., 2003]. Dr.
Lemoine recounted the observations in
127 children, 112 of whom had alcoholic mothers (sometimes with alcoholic
fathers) and 15 of whom had only
alcoholic fathers. This report makes
particular mention of the distinctive
facies and deﬁcient growth in these
children. This report was not widely
appreciated, and it was not until 1973
that Jones et al. put fetal alcohol
syndrome on the map based on a report
of eight affected children [Jones et al.,
1973]. Dr. Lemoine recounted the
The ﬁrst report of what is
now known as fetal alcohol
syndrome was published by
Lemoine, a French physician,
and his coworkers in 1968.
Dr. Lemoine recounted the
observations in 127 children,
112 of whom had alcoholic
mothers (sometimes with
alcoholic fathers) and 15 of
whom had only alcoholic
fathers. This report makes
particular mention of the
distinctive facies and deﬁcient
growth in these children.
This report was not widely
appreciated, and it was not until
1973 that Jones et al. put fetal
ARTICLE
alcohol syndrome on the map
based on a report of eight
affected children.
story some years later, observing wryly
that his 127 cases had not made much of a
splash and that he was grateful for the eight
American cases that brought recognition
to the problem [Lemoine, 2003].
Commonly encountered effects of
fetal alcohol syndrome are prenatal and
postnatal growth deﬁciency (97%), microcephaly (93%), and mental deﬁciency
(89%) [Hanson et al., 1976]. Anatomical
evaluation of the brain demonstrates
microcephaly, hydrocephaly, cerebral
dysgenesis, corpus callosum anomalies,
and cerebelar anomalies [Roebuck et al.,
1998]. Other features include short
palpebral ﬁssures, a long smooth philtrum, thin upper lip, joint anomalies,
and cardiac septal defects [Hanson et al.,
1976; Clarren, 1981; Jones, 1986].
The incidence of fetal alcohol
syndrome among the offspring of alcoholic women has been estimated as
anywhere from 4.3% [Abel, 1995] to
40% [Jones, 1986]. Alcohol consumption during pregnancy has also been
associated with an increase risk of other
adverse outcomes. Florey et al. [1992]
reported that consumption of more than
120 g of alcohol per week was associated
with spontaneous abortion (odds ratio
2.3, 95% conﬁdence interval 1.1–4.5).
An association between second trimester
pregnancy loss and consumption of
more than 3 drinks/day has also been
reported (relative risk 3.5, 95% conﬁdence interval 1.8–7.0) [Harlap and
Shiono, 1980]. Women who drink >5
drinks per week compared to women
who drink <1 drink per week are at
increased risk of delivering a stillborn
baby (relative risk 2.96, 95% conﬁdence
interval 1.37–6.41) [Kesmodel et al.,
2002]. Binge drinking three or
more times during a pregnancy was
associated with stillbirth (hazard ratio
1.56, 95% conﬁdence interval 1.01–2.4)
[Strandberg-Larsen et al., 2008].
Among the issues that limit the
assessment of outcomes in women with
ARTICLE
presumed light to moderate alcohol
intake are self-reporting of use, variability of drinking patterns, quantiﬁcation
and strength of the alcohol consumed,
diet, and smoking status [Wallpole et al.,
1990]. Although it can be assumed that
there is an intake of ethanol during
pregnancy that is too low to cause
adverse effects on the offspring, we do
not know what that intake might be.
Maternal intake as low as three drinks/
week has been associated with an
increase in intrauterine growth restriction [Windham et al., 1995]. For this
reason, current counseling practice is to
recommend that pregnant women
avoiding drinking alcohol entirely.
Toluene Abuse
Recreational inhalation of toluene by
pregnant women has been associated
with microcephaly, mental retardation,
and dysmorphic features similar to those
in fetal alcohol syndrome. The ﬁrst
report of the association was published
by Toutant and Lippmann [1979] who
noted small body size, microcephaly, a
ﬂat nasal bridge, hypoplastic mandible,
short palpebral ﬁssures, mildly low-set
ears, sacral dimple, sloping forehead, and
uncoordinated arm movements in a
child born to a woman who abused
toluene and ethanol. The mother presented with ataxia, tremor, sensory
deﬁcits, memory impairment, and poor
intellectual functioning attributed to her
toluene addiction.
Other case reports followed. The
ﬁrst denominator-based report of any
size was published by Wilkins-Haug and
Gabow [1991]. Ten toluene-abusing
women were systematically identiﬁed
and their 21 toluene-exposed pregnancies were evaluated. Preterm delivery
occurred in 86%, perinatal death in 14%,
and intrauterine growth restriction in
72%, more often than expected in the
general population. Fetal alcohol syndrome-like features were noted in three
of the children, but it is not clear how
carefully the other children were evaluated for dysmorphic features. Pearson
et al. [1994] reported that half of children
born to toluene-abusing women
were growth-restricted, two-thirds had
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
microcephaly, 80% had developmental
delay, and nearly 90% had dysmorphic
features similar to fetal alcohol syndrome
or had other minor anomalies. These
authors believed they could distinguish
toluene from ethanol effects: children
affected by toluene were more likely to
be premature and to have micrognathia,
abnormal ears, narrow bifrontal diameter, abnormal scalp hair patterning, nail
hypoplasia, downturned mouth corners,
large anterior fontanel, and abnormal
muscle tone; children affected by ethanol were more likely to have prenatal
microcephaly, thin upper lip, smooth
philtrum, small nose, and altered palmar
creases.
In experimental animal studies,
inhalation exposure or gavage treatment
with toluene increase the incidence of
abnormal embryo development only at
very high exposure levels intended to
model human recreational use. The
most consistent effects at these high
exposure levels are reductions in fetal
body weight and viability [Gospe et al.,
1994, 1996; Bowen et al., 2005, 2009].
Among the structural alterations that
have been described in various mouse
and rat studies are cleft palate, short or
missing digits, missing limbs, misshapen
scapula, missing and supernumerary
vertebrae and ribs, fused digits, cryptorchidism, displaced abdominal organs,
microgastria or gastromegaly, distended/hypoplastic bladder, and small
atria. These abnormalities are not suggestive of the ﬁndings in children born
to toluene-abusing women, and an
experimental animal model mimicking
all the features of toluene embryopathy
has not been developed.
Toluene abuse has been estimated to
involve inhalation of at least 800 ppm
and usually in excess of 10,000 ppm
[Bowen et al., 2005]. Women who abuse
toluene commonly have renal tubular
acidosis and in some cases, their offspring
have associated transient acidosis and
electrolyte abnormalities [Goodwin,
1988]. It is not known whether the
acidosis or electrolyte abnormalities
contribute to any of the adverse effects
on fetal development associated with
toluene abuse. Moreover, many women
who report toluene abuse also report
13
abuse of other substances. These other
exposures or other factors associated
with the abusers’ lifestyles may be at
play in the effects on the offspring. The
identiﬁcation of toluene abuse as a
teratogenic exposure appears to require
the abuse component as much as the
toluene component. It has been estimated that occupational exposure to toluene
(<100 ppm) does not pose a signiﬁcant
fetal risk [Wilkins-Haug, 1997].
PHYSICAL AGENTS
X-Ray
X-rays are a class of electromagnetic
radiation with a characteristically short
wavelength used in both diagnostic
imaging and in therapy. These electromagnetic waves are energetic enough to
detach electrons from their orbits, resulting in ionization, and the ionization
results in tissue damage.
During the early 1920s, case reports
suggested an association between decreased infant head size and mental
retardation in children born to women
exposed to 60 rad (cGy) ionizing radiation during pregnancy [reviewed by
Miller, 2004]. Small head size was
reported with doses as low as 20 rad.
Data from the atomic bombing of
Hiroshima and Nagasaki identiﬁed the
period of greatest susceptibility to the
fetus as between 8 and 15 weeks of
gestation, with no demonstrated risk at
less than 8 weeks [Hal, 1991].
Severe intellectual disability from
ionizing radiation occurs in about 40%
of offspring after exposure to 100 rad and
60% of offspring after exposure to
150 rad [Hal, 1991]. In a well-known
analysis, Otake and Schull [1984] suggested that any dose of radiation between
8 and 15 weeks of gestation could
increase the risk of mental retardation
and microcephaly by an estimated 0.4%
per rad [ICRP, 1986]. The Otake and
Schull analysis was based on a small
number of patients with varying and
uncontrolled sources of radiation and is
not easily comparable to the ﬁltered
radiation used in diagnostic radiology.
Contemporary thought, however, holds
that there is a threshold exposure level
14
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
below which there is no increase in the
risk of microcephaly and mental retardation; that level is placed at 20 rad, a
threshold supported by experimental
animal studies [Brent, 1989, 2006].
The threshold for counseling purposes
is often placed at 5 rad (5,000 mrad) to
provide a margin of safety. Diagnostic
studies do not result in this level of
embryofetal exposure (Fig. 4), and most
pregnant women with a history of
diagnostic X-ray exposure do not have
an increase in risk of bearing a child with
congenital malformations over that of
the general population.
Intrauterine X-ray exposure may
increase the risk of childhood malignancy including leukemia [Harvey et al.,
1985]. It has been estimated that 1/2,000
(0.05%) children exposed to x-ray
pelvimetry will develop leukemia compared to a baseline risk of 1/3,000
(0.03%) [Brent, 2006]. This increase is
equivalent to an additional case of
childhood leukemia for every 6,000
exposed fetuses.
INFECTIONS
Rubella
In 1941, congenital cataract was associated with rubella virus infection during
pregnancy by Norman Gregg, an Australian ophthalmologist. The story of
Gregg’s discovery was reviewed by
Webster [1998]. Gregg had seen 13
infants with bilateral cataracts during
the previous year and collected 65
additional cases from coworkers in
Australia. A deﬁnite history of rubella
infection was obtained from 68 of the 78
mothers. Many of these children had
difﬁculty feeding, suggesting congenital
heart disease. By the time of Gregg’s
paper, 15 of the children had died with
autopsy conﬁrmation of heart defects.
The congenital rubella syndrome was
considered to have been accepted when
Wesselhoeft published his detailed
review of reports by Gregg and a number
of others indicating that of 573 pregnancies with rubella infection, there were
521 abnormal and 52 normal babies for
an attack rate of about 90% [Wesselhoeft,
1947].
Although maternal infection with
rubella virus can affect any fetal organ,
most congenital anomalies affect the
eyes, heart, brain, and ears. Deafness is
the most common consequence, but
cardiac disease and mental retardation
also occur frequently. In addition, the
newborn may exhibit poor growth,
thrombocytopenia, and encephalitis
[Menser et al., 1967; Webster, 1998;
Forrest et al., 2002]. If the infection
occurs in the ﬁrst 12 weeks of gestation
about 80% of fetuses will be born with
congenital anomalies. Between 12 and
16 weeks some 50% of fetuses will be
affected [Miller et al., 1982; Webster,
1998]. After 17 weeks the risk of
congenital defects is signiﬁcantly less.
With infection after16 or 17 weeks the
most common ﬁnding is deafness; all
other anomalies occur with infection in
the ﬁrst trimester.
In 1966, Parkman et al. developed
the ﬁrst live attenuated rubella vaccine
Figure 4. Exposure of the conceptus from diagnostic x-ray studies. Drawn from data
in American College of Obstetricians and Gynecologists [2004].
ARTICLE
[Parkman et al., 1966]; the vaccine was
available in the US in 1969 [Parkman,
1999]. Thereafter, the incidence of
congenital rubella has signiﬁcantly decreased. Although live vaccines are not
recommended for administration during
pregnancy, there have been no reports of
adverse pregnancy outcome attributed to
rubella vaccine. The Centers for Disease
Control and Prevention summarized
reports on 210 women who received
the vaccine in the ﬁrst trimester. These
women delivered 212 healthy infants
[The Centers for Disease Control, 1989].
Varicella
Vareicella-zoster virus is responsible for
both chickenpox and herpes zoster
(shingles). More than 80% of children
have chickenpox by the time they reach
10 years of age. Some women who are
seronegative can reach childbearing age
and have a primary infection during
their pregnancy. Varicella complicates
0.5–0.7/1,000 pregnancies [Sever and
White, 1968]. Maternal effects can range
from a chickenpox rash to a more severe
viral pneumonia.
After the association between rubella infection and congenital malformations was recognized, there was
interest in identifying the potential
effects of other viral infections on
pregnancy outcome. The ﬁrst published
report of a pregnancy complicated by
varicella was presented in 1945 [Conte
et al., 1945]. The child was described as
normal. The ﬁrst case report of a child
with abnormalities after maternal varicella followed 2 years later [Laforet and
Lynch, 1947]. The woman delivered the
child at term after a diagnosis of varicella
at 8 weeks gestation. She had had a viral
exanthem and a fever of 102 F lasting
2 weeks. The child had an undescended
left testicle, atrophied right leg with
anomalous digits, cortical atrophy, hydrocephalus, and a relaxed anus.
Transmission of varicella zoster
virus to the fetus occurs in 25% of
primary maternal infections, half of
which will be symptomatic [Paryani
and Arvin, 1986; Pastaszak et al.,
1994]. Infection may result in skin
scarring and organ necrosis. Features of
ARTICLE
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
TABLE IV. Maternal Infections Associated With Developmental Toxicity
Infection
Cytomegalovirus
(CMV; a DNA
herpesvirus)
Varicella zoster
virus (VZV;
a DNA
herpesvirus)
Rubella
(an RNA virus)
Parvovirus B19
(a DNA virus)
Toxoplasmosis
(a protozoan)
Effects
Jaundice, petichiae,
thrombocytopenia,
hepatosplenomegaly, growth
restriction, non-immune
hydrops
Long term: developmental
delay, seizures, sensorineural
hearing loss
Spontaneous abortion,
intrauterine fetal demise,
hydrops, polyhydramnios
Varicella embryopathy: limb
hypoplasia, scars, malformed
appendages, muscular
atrophy, microcephaly,
cortical atrophy, cataracts,
chorioretinitis,
microophthalmia,
psychomotor retardation
Sensorineural hearing loss,
growth retardation,
miscarriage, stillbirth, heart
defects, cataracts, glaucoma,
retinitis, microcephaly,
micropthalmia, intrauterine
growth restriction, cerebral
palsy, mental retardation
Fetal death, hydrops,
spontaneous abortion
Mental retardation, chorioretinitis,
periventricular calciﬁcations,
seizures, ventriculomegaly,
chorioretinitis,
hepatosplenomegaly, fever,
ascites, rash
Prevalence of
effects after
infection
Sensitive
period
Comments
24% sensorineural hearing
loss; 32% CNS sequelae
First
trimester
Primary infection: 5–18 %
children experience serious
sequelae (especially ﬁrst half
of pregnancy)
2.5% sensorineural hearing
loss; 15% CNS
sequelae
Second
trimester
0.4%
<13 weeks
Most common congenital
infection
Leading cause of sensorineural
hearing loss
0.7–4% primary CMV
infection rate among
pregnant women in US
Risk of transmission to the fetus
is 30–40%
Respiratory droplets
2%
13–20 weeks
Neonatal VZV has 20–30%
mortality rate
67%
<12 weeks
Transmission by respiratory
droplets
35%
13–16 weeks
19%
1–12 weeks
Seen mostly in pregnancies in
women born outside the US
Infection <12 weeks associated
with greater severity of fetal
effects
Fetal defects rare with infection
after 16 weeks
Respiratory secretions
15%
13–20 weeks
6%
>20 weeks
Congenital toxoplasmosis
occurs in 1/8,000
pregnancies
Transmission rate
10–15%
25%
60%
All trimesters
can be
affected
1st trimester
2nd trimester
3rd trimester
Fetal infection in 33% of
maternal infections
Fetal death 11% with infection
<20 weeks
Cat feces
Infected meat
Congenital toxoplasmosis is
rare with chronic maternal
infection
(Continued )
15
16
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
ARTICLE
TABLE IV. (Continued )
Infection
Syphilis
(Treponema
palladium;
a spirochete)
Listeria (a gram
positive
bacterium)
Prevalence of
effects after
infection
Effects
Early congenital syphilis:
hepatosplenomegaly, hydrops,
intrauterine growth restriction,
osteochondritis, jaundice,
anemia, skin lesions, rhinitis,
CNS involvement,
chorioretinitis
Early latent syphilis: stillbirths,
miscarriage, preterm delivery
Late congenital syphilis:
Hutchinson’s teeth, deafness,
mental retardation,
hydrocephalus, palsies, frontal
bossing, saddle nose, saber shin,
protuberant mandible
Late miscarriage, stillbirth,
preterm delivery
Sensitive
period
Comments
8.8 cases/100,000
pregnancies
Early latent: 20%
prematurity, 10%
stillbirths, 4% neonatal
death, 40% congenital
syphilis, 20% normal
Late latent: 9% prematurity,
10% stillbirths, 1%
neonatal death, 10%
congenital syphilis,
70% normal
50% perinatal mortality
10% mortality among live
born infants
Measles
(an RNA virus)
Spontaneous abortion, preterm
delivery
20–60%
Herpes simplex
(HSV; a DNA
herpesvirus)
Skin vesicles, scarring,
microcephaly, hydranencephaly,
disseminated infection
Questionable intrauterine growth
restriction with third trimester
infection
50–60% mortality with
disseminated infection
At delivery
15% mortality with
encephalitis
Sequelae in 50% of
survivors
Food borne: luncheon meats,
soft cheeses, smoked seafood
Flu like symptoms
Symptoms of food poisoning
Septicemia, pneumonia,
meningitis in the mother
Respiratory droplets
Pregnant women are 2 times
more likely to be hospitalized,
3 times more likely to have
pneumonia, 6 times likely to
die from complications than
nonpregnant women
No increased risk of
malformations
There has been an association of
measles exposure at birth and
Hodgkin’s disease in children
Maternal fetal transmission
during delivery
Most often from primary
infections rather than
recurrences
Fetal HSV infection in 1/200,000
deliveries
Neonatal HSV in 1/3,500
deliveries
Risk of neonatal HSV after
primary infection 50%, after
recurrent infection 0–3%
70% of neonatal herpes is caused
by HSV-2
Hitchcock et al. [1999], Gabbe et al. [2007], and DeCherney et al. [2007].
congenital varicella syndrome include
scarring in a dermatomal pattern, cataract, microphthalmia, chorioretinitis,
microcephaly, mental retardation, and
dysfunction of the bowel or bladder
sphincter [Pastaszak et al., 1994].
Peak susceptibility to varicella
embryopathy occurs with infection be-
tween 8 and 20 weeks gestation when
the virus is most likely to damage neural
tissue [Enders, 1984; Alkalay et al.,
1987]. Women who contract varicella
ARTICLE
in the ﬁrst 20 weeks of gestation have
about a 1.2% risk of a child with varicella
embryopathy [Enders et al., 1994; Jones
et al., 1994; Pastaszak et al., 1994].
Varicella infection prior to 13 weeks
gestation is associated with embryopathy
considerably less often, and maternal
zoster appears to entail little if any risk for
the fetus [Enders et al., 1994].
Other Infections
Other infectious agents may be responsible for developmental toxicity in
exposed pregnancies. These exposures
are summarized in Table IV.
REFERENCES
Abel EL. 1995. An update on incidence of FAS:
FAS is not an equal opportunity birth defect.
Neurotoxicol Teratol 17:437–443.
Adam M, Manning M, Beck A, Kwan A, Enns
GM, Clericuzio C, Hoyme HE. 2003.
Methotrexate/misoprostol embryopathy:
Report of four cases resulting from failed
medical abortion. Am J Med Genet Part A
123A:72–78.
Adams J. 2004. The adverse effect proﬁle of
neurobehavioral teratogens: Retinoic acid.
Birth Defects Res Part A Clin Mol Teratol
70:279.
Adams J, Lammer EJ. 1993. Neurobehavioral
teratology of isotretinoin. Reprod Toxicol
7:175–177.
Alkalay AL, Pomerance JJ, Rimoin DL. 1987.
Fetal varicella syndrome. J Pediatr 111:320–
323.
American College of Obstetricians and Gynecologists. 2004. Guidelines for diagnostic
imaging during pregnancy. Committee
Opinion number 299. Washington, DC:
American College of Obstetricians and
Gynecologists.
Barbero P, Valdez R, Rodrı́uez H, Tiscornia C,
Mansilla E, Allons A, Coll S, Liascovich R.
2008. Choanal atresia associated with maternal hyperthyroidism treated with methimazole: A case–control study. Am J Med Genet
Part A 146A:2390–2395.
Bavnick JN, Weaver DD. 1986. Subclavian artery
supply disruption sequence: Hypothesis of a
vascular etiology for Poland, Klippel-Feil
and Mobius anomalies. Am J Med Genet
23:903–918.
Bérard A, Azoulay L, Koren G, Blais L, Perreault
S, Oraichi D. 2007. Isotretinoin pregnancies, abortions and birth defects: A population-based perspective. Br J Clin Pharmacol
63:196–205.
Bertollini R, Källen B, Mastroiacovo P, Robert E.
1987. Anticonvulsant drugs in monotherapy. Effect on the fetus. Eur J Epidemiol
3:164–171.
Binkerd PE, Rowland JM, Nau H, Hendrickx
AG. 1988. Evaluation of valproic acid (VPA)
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
developmental toxicity and pharmacokinetics in Sprague–Dawley rats. Fundam
Appl Toxicol 11:485–493.
Bjerkedal T, Czeizel A, Gouiard J, Källén B,
Mastroiacova P, Nevin N, Oakley G Jr,
Robert E. 1982. Valproic acid and spina
biﬁda. Lancet 2:1096.
Bowen SE, Battis JC, Mohammadi MH, Hannigan JH. 2005. Abuse pattern of gestational
toluene exposure and early postnatal development in rats. Neurotoxicol Teratol
27:105–116.
Bowen SE, Irtenkauf S, Hannigan JH, Stefanski
AL. 2009. Alterations in rat fetal morphology following abuse patterns of toluene
exposures. Reprod Toxciol 27:161–169.
Brent RL. 1989. The effects of embryonic and
fetal exposure to X-ray, microwaves, and
ultrasound: Counseling the pregnant and
nonpregnant patient about these risks.
Semin Oncol 16:347–368.
Brent RL. 2006. Counseling patients exposed to
ionizing radiation during pregnancy. Rev
Panam Salud Publica 20:198–204.
Brown NA, Kao J, Fabro S. 1980. Teratogenic
potential of valproic acid. Lancet 1:660–661.
Buehler BA, Delimont D, van Waes M, Finnell
RH. 1990. Prenatal prediction of risk of the
fetal hydantoin syndrome. N Engl J Med
322:1567–1572.
Buttar H. 1997. An overview of the inﬂuence of
ACE inhibitors on fetal-placental circulation
and perinatal development. Mol Cell Biochem 176:61–71.
Camera G, Pregliasco P. 1992. Ear malformation
in baby born to mother using tretinoin
cream. Lancet 339:687 only.
Carey JC, Martinez L, Balken E, Leen-Mitchell
M, Robertson J. 2009. Determination of
human teratogenicity by the astute clinician
method: Review of illustrative agents and a
proposal of guidelines. Birth Defects Res A
Clin Mol Teratol 85:63–68.
Centers for Disease Control. 1989. Rubella
vaccination during pregnancy—United
States, 1971–1988. MMWR 38:289–293.
Chan WS, Anand S, Ginsberg JS. 2000. Anticoagulation of pregnant women with
mechanical heart valves: A systematic review
of the literature. Arch Intern Med 160:191–
196.
Chapa JB, Hibbard JU, Weber EM, Abramowicz
JS, Verp MS. 2003. Prenatal diagnosis of
methotrexate embryopathy. Obstet Gynecol
101:1104–1107.
Chisholm CA, Chescheir NC, Kennedy M. 1997.
Reversible oligohydramnios in a pregnancy
with angiotensin-converting enzyme inhibitor exposure. Am J Perinatol 14:511–513.
Clarren SK. 1981. Recognition of fetal alcohol
syndrome. JAMA 245:2436–2439.
Conte WR, McCammon CS, Christie A. 1945.
Congenital defects following maternal
rubella. Am J Dis Child 70:301–306.
Cooper DS, Rivkees SA. 2009. Putting propylthiouracil in perspective. J Clin Endocrinol
Metab 94:1881–1882.
Cooper WO, Hernandez-Diaz S, Arbogast PG,
Dudley JA, Dyer SD, Gideon PS, Hall K,
Ray WA. 2006. Major congenital malformations after ﬁrst-trimester exposure to
ACE inhibitors. N Engl J Med 354:2443–
2451.
17
Cotrufo M, De Feo M, De Santo LS, Romano G,
Della Corte A, Renzulli A, Gallo C. 2002.
Risk of warfarin during pregnancy with
mechanical valve prostheses. Obstet Gynecol 99:35–40.
da Silva Dal Pizzol TS, Knop FP, Mengue SS.
2006. Prenatal exposure to misoprostol and
congenital anomalies: Systematic review and
meta analysis. Reprod Toxicol 22:666–671.
da Silva Dal Pizzol TS, Sanseverino MTV,
Mengue SS. 2008. Exposure to misoprostol
and hormones during pregnancy and risk of
congenital anomalies. Cad Saude Publica
24:1447–1453.
De la Cruz E, Sun S, Vangvanichyakorn K,
Desposito F. 1984. Multiple congenital
malformations associated with maternal
isotretinoin therapy. Pediatrics 74:428–
430.
DeCherney AH, Nathan L, Goodwin TM,
Lauder N, editors. 2007. Current diagnosis
and treatment: Obstetrics and gynecology.
10th edition. New York: McGaw-Hill.
DeSesso JM, Goeringer GC. 1992. Methotrexateinduced developmental toxicity in rabbits is
ameliorated by 1-(p-tosyl)-3,4,4-trimethylimidazolidine, a functional analog for
tetrahydrofolate-mediated
one-carbon
transfer. Teratology 45:271–283.
Di Gianantonio E, Schaefer C, Mastroiacovo PP,
Cournot MP, Benedicenti F, Reuvers M,
Occupati B, Robert E, Bellemin B, Addis A,
Arnon J, Clementi M. 2001. Adverse effects
of prenatal methimazole exposure. Teratology 64:262–266.
Diav-Citrin O, Ornoy A. 2002. Teratogen update:
Antithyroid drugs-methimazole, carbimazole, and propylthiouracil. Teratology
65:38–44.
Diav-Citrin O, Shechtman S, Arnon J, Ornoy A.
2001. Is carbamazepine teratogenic? A
prospective controlled study of 210 pregnancies. Neurology 57:321–324.
Diav-Citrin O, Shechtman S, Halberstadt Y,
Finkel-Pekarsky V, Wajnberg R, Arnon J,
Di Gianantonio E, Clementi M, Ornoy A.
2011. Pregnancy outcome after in utero
exposure to angiotensin converting enzyme
inhibitors or angiotensin receptor blockers.
Reprod Toxicol 31:540–545.
Disaia PJ. 1966. Pregnancy and delivery of a
patient with a Starr-Edwards mitral valve
prosthesis. Obstet Gynecol 28:469–472.
Dubick MA, Keen CL, Rucker RB. 1985. Elastin
metabolism during perinatal lung development in the copper-deﬁcient rat. Exp Lung
Res 8:227–241.
Edmonds LD, Oakley GP. 1990. Ebstein’s anomaly and maternal lithium exposure during
pregnancy. Teratology 41:551–552 (http://
toxnet.nlm.nih.gov/cgi-bin/sis/search/r?./
temp/NewkB2:@andþ@auþ@termþ
EdmondsþLD).
Enders G. 1984. Varicella-zoster virus infection in
pregnancy. Prog Med Virol 29:166–196.
Enders G, Bolley I, Miller E, Cradock-Watson J,
Ridehalgh M. 1994. Consequences of
varicella and herpes zoster in pregnancy:
Prospective study of 1739 cases. Lancet
343:1548–1551.
Endres W. 1981. D-Penicillamine in pregnancy—
To ban or not to ban? Klin Wochenschr
59:535–537.
18
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
Eroğlu E, Gökçil Z, Bek S, Ulas, UH, Odabas
,i Z.
2008. Pregnancy and teratogenicity of antiepileptic drugs. Acta Neurol Belg 108:53–
57.
Fantel AG, Shepard TH, Newell-Morris LL,
Moffett BC. 1977. Teratogenic effects of
retinoic acid in pigtail monkeys (Macaca
nemestrina) I. General features. Teratology
15:65–71.
Feldkamp M, Carey JC. 1993. Clinical teratology
counseling and consultation case report:
Low dose methotrexate exposure in the
early weeks of pregnancy. Teratology
47:533–539.
Finnell RH, Dansky LV. 1991. Parental epilepsy,
anticonvulsant drugs, and reproductive outcome: Epidemiologic and experimental
ﬁndings spanning three decades; 1: Animal
studies. Reprod Toxicol 5:281–299.
Florey C, Taylor D, Bolumar F, Kaminski M,
Olsen J. editors. 1992. EUROMAC. A
European concerted action: Maternal alcohol consumption and its relationship with
the outcome of pregnancy and child development at 18 months. Int J Epidemiol
21:S38–S39.
Fonesca W, Alencar AJ, Mota FS, Coelho HL.
1991. Misoprostol and congenital malformations. Lancet 338:56 only.
Forrest JM, Turnbull FM, Sholler GF. 2002.
Gregg’s congenital rubella patients 60 years
later. Med J Aust 177:664–667.
Gabbe SD, Simpson SL, Niebyl JR, Galan H,
Goetzl L, Jauniaux ERM, Landon M,
editors. 2007. Obstetrics: Normal and
problem pregnancies. 5th edition. Philadelphia: Churchill Livingstone.
Ghafari A, Sanadgol H. 2008. Pregnancy after
renal transplantation: Ten-year single-center
experience. Transplant Proc 40:251–252.
Goldberg JM, Falcone T. 1999. Effect of diethylstilbestrol on reproductive function. Fertil
Steril 72:1–7.
Golderg AB, Greensberg BS, Darney PD. 2001.
Misoprostol and pregnancy. N Engl J Med
344:38–46.
Gonzalez CH, Marques-Dias MJ, Kim CA,
Sugayama SM, Da Paz JA, Huson SM,
Holmes LB. 1998. Congenital abnormalities
in Brazilian children associated with misoprostol misuse in the ﬁrst trimester of
pregnancy. Lancet 351:1624–1627.
Goodwin TM. 1988. Toluene abuse and renal
tubular acidosis in pregnancy. Obstet Gynecol 71:715–718.
Gospe SM Jr, Saeed DB, Zhou SS, Zeman FJ.
1994. The effects of high-dose toluene on
embryonic development in the rat. Pediatr
Res 36:811–814.
Gospe SM Jr, Zhou SS, Saeed DB, Zeman FJ.
1996. Developmental of a rat model of
toluene-abuse embryopathy. Pediatr Res
40:82–87.
Goulding EH, Pratt RM. 1986. Isotretinoin
teratogenicity in mouse whole embryo
culture. J Caniofac Genet Dev Biol 6:99–
112.
Gralla EJ, McIlhenny HM. 1972. Studies in
pregnant rats, rabbits and monkeys with
lithium carbonate. Toxicol Appl Pharmacol
21:428–433.
Guignard JP, Burgener F, Calaine A. 1981.
Persistent anuria in a neonate: a side effect
of captopril? Int J Pediatr Nephrol 2:133.
Hal EJ. 1991. Scientiﬁc view of low-level
radiation risks. Radiographics 11:509–518.
Hall BD. 1989. Warfarin embryopathy and
urinary tract anomalies: Possible new association (letter). Am J Med Genet 34:292–
293.
Hall JG, Pauli RM, Wilson KM. 1980. Maternal
and fetal squeal of anticoagulation during
pregnancy. Am J Med 68:122–140.
Hanson JW, Jones KL, Smith DW. 1976. Fetal
alcohol syndrome—Experience with 41
patients. JAMA 235:1458–1460.
Hanson JW, Smith DW. 1975. The fetal hydantoin
syndrome. J Pediatr 87:285–290.
Harlap S, Shiono PH. 1980. Alcohol, smoking
and incidence of spontaneous abortions in
the ﬁrst and second trimester. Lancet
2:173–176.
Harpey JP, Jaudon MC, Calvel JP, Galli A, Darbois
Y. 1983. Cutis lax and low serum zinc after
antenatal exposure to penicillamine. Lancet
2:858 only.
Harrod MJE, Sherrod PS. 1981. Warfarin embryopathy in siblings. Obstet Gynecol 57:673–
676.
Harvey EB, Boyce JD Jr, Honey man M, Flannery
JT. 1985. Prenatal X-ray exposure and
childhood cancer in twins. N Engl J Med
312:541–545.
Hendrickx AG, Nau H, Binkerd P, Rowland JM,
Rowland JR, Cukierski MJ, Cukierski MA.
1988. Valproic acid developmental toxicity
and pharmacokinetics in the rhesus monkey:
An interspecies comparison. Teratology
38:329–345.
Herbst AL, Ulfelder H, Poskanzer DC. 1971.
Adenocarcinoma of the vagina. Association
of maternal stilbestreol therapy with tumor
appearance in young women. N Engl J Med
284:878–881.
Herndández-Dı́az S, Mittendorf R, Holmes LB.
2010. Comparative safety of topiramate
during pregnancy. Birth Defects Res (Part
A) 88:408 only.
Hiilesma VK, Brady AH, Granstron M-L, Teramo
KAW. 1980. Valproic acid during pregnancy.
Lancet 1:883.
Hill AB. 1965. The environment and disease:
Association or causation? Proc R Soc Med
58:295–300.
Hitchcock PJ, MacKay HT, Wasserheit JN,
editors. 1999. Sexually transmitted diseases
and adverse outcomes of pregnancy. Washington, DC: American Society for Microbiology.
Hoberman AM, Deprospo JR, Lochry EA,
Christian MS. 1990. Developmental toxicity
study of orally administered lithium hypochlorite in rats. J Am Coll Toxicol 9:367–
379.
Hoeltzenbein M, Elefant E, Garayt Ornoy A,
Clementi M, Manakova E, Merlob P,
Rodrı́guez-Pinilla E, Rothuizen L, Smorlesi
C, te Winkel B, de Santis M, Stephens S,
Vial T, Weber-Schoendorfer C, Schaefer C.
2010. Maternal exposure to mycophenolate
mofetil in pregnancy—Results of the
ENTIS collaborative study. Reprod Toxicol
30:228 only.
Holmes LB, Baldwin EJ, Smith CR, Habecker E,
Glassman L, Wong SL, Wyszynski DF. 2008.
Increased frequency of isolated cleft palate in
infants exposed to lamotrigine during
pregnancy. Neurology 70:2152–2158.
ARTICLE
Howe AM, Webster WS. 1992. The warfarin
embryopathy: A rat model showing maxillonasal hypoplasia and other skeletal disturbances. Teratology 46:379–390.
International Commission on Radiological Protection. 1986. Developmental effects of
irradiation on the brain of the embryo and
fetus. Ann ICRP 16:1–43.
Irino M, Sanada H, Tashiro S, Yasuhira K, Takeda
T. 1982. D-Penicillamine toxicity in mice.
III. Pathological study of offspring of
penicillamine-fed pregnant and lactating
mice. Toxicol Appl Pharmacol 65:273–285.
Iturbe-Alessio I, Fonseca MC, Mutchinik O,
Santos MA, Zajarı́as A, Salazar E. 1986.
Risks of anticoagulant therapy in pregnant
women with artiﬁcial heart valves. N Engl J
Med 315:1390–1393.
Jacobson SJ, Jones K, Johnson K, Ceolin L, Kaur
P, Sahn D, Donnenfeld AE, Rieder M,
Santelli R, Smythe J, Pastuszak A, Einarson
T, Koren G. 1992. Prospective multicentre
study of pregnancy outcome after lithium
exposure during ﬁrst trimester. Lancet
339:530–533.
Janz D, Fuchs U. 1964. Are anti epileptic drugs
harmful during pregnancy? Dtsch Med
Wschr 89:241–248.
Jefferies JA, Robboy SJ, O’Brien PC, Bergstralh
EJ, Labarthe DR, Barnes AB, Noller KL,
Hatab PA, Kaufman RH, Townsend DE.
1984. Structural anomalies of the cervix and
vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project. Am J
Obstet Gynecol 148:59–66.
Jentink J, Loane MA, Dolk H, Barisic I, Garne E,
Morris JK, de Jong-van den Berg LTW, for
the EUROCAT Antiepileptic Study Working Group. 2010. Valproic acid monotherapy in pregnancy and major congenital
malformations. N Engl J Med 362:2185–
2193.
Jick SS, Terris BZ, Jick H. 1993. First trimester
topical tretinoin. Lancet 341:1181–1182.
Johansen KT. 1971. Lithium teratogenicity. Lancet 1:1026–1027.
Jones KL. 1986. Fetal alcohol syndrome. Pediatr
Rev 8:122–126.
Jones KL, Smith DW, Ulleland CN, Streissguth P.
1973. Pattern of malformation in offspring
of chronic alcoholic mothers. Lancet
301:1267–1271.
Jones KL, Lacro RV, Johnson KA, Adams J. 1989.
Pattern of malformations in the children of
women treated with carbamazepine during
pregnancy. N Engl J Med 320:1661–1666.
Jones KL, Johnson KA, Chambers CD. 1994.
Offspring of women infected with varicella
during pregnancy: A prospective study.
Teratology 49:29–32.
Jurand A. 1988. Teratogenic activity of lithium
carbonate: An experimental update. Teratology 38:101–111.
Källén B. 1988. Comments on teratogen update:
Lithium. Teratology 38:597 only.
Kalter H. 2003. Teratology in the 20th century.
Environmental causes of congenital malformations in humans and how they were
established. Neurotoxicol Teratol 25:131–
282.
Keen CL, Mark-Savage P, Lönnerdal B, Hurley
LS. 1982. Teratogenesis and low copper
status resulting from D-penicillamine in rats.
Teratology 26:163–165.
ARTICLE
Keen CL, Mark-Savage P, Lönnerdal B, Hurley
LS. 1983. Teratogenic effects of D-penicillamine in rats: Relation to copper deﬁciency.
Drug Nutr Interact 2:17–34.
Kerber IJ, Warr OS III, Richardson C. 1968.
Pregnancy in a patient with a prosthetic
mitral valve. Associated with a fetal anomaly
attributed to warfarin sodium. JAMA
203:223–225.
Kilbourn KH, Hess RA. 1982. Neonatal deaths
and pulmonary dysplasia due to D-penicillamine in the rat. Teratology 26:1–9.
Klieger-Grossmann C, Chitayat D, Lavigne S, Kao
K, Garcia-Bournissen F, Quinn D, Lio V,
Sermer M, Riordan S, Laskin C, Matok I,
Gorodischer R, Chambers C, Levi A, Koren
G. 2010. Prenatal exposure to mycophenolate mofetil: An updated estimate. J Obstet
Gynaecol Can 32:794–797.
Kochhar DM, Penner JD. 1987. Developmental
effects of isotretinoin and 4-oxo-isotretinoin: The role of metabolism in teratogenicity. Teratology 36:67–75.
Laforet EG, Lynch CL. 1947. Multiple congenital
defects following maternal varicella. New
Engl J Med 236:534–537.
Lammer EJ. 1988. Embryopathy in infant conceived one year after termination of maternal etretinate. Lancet 2:1080–1081.
Lammer EJ, Chen DT, Hoar RM, Agnish ND,
Benke PJ, Braun JT, Curry CJ, Fernhoff
PM, Grix AW, Lott IT, Richard JM, Sun
SC. 1985. Retinoic acid embryopthy. N
Engl J Med 313:837–841.
Laver M, Fairley KF. 1971. D-Penicillamine
treatment in pregnancy. Lancet 1:1019–
1020.
Lemoine P. 2003. The history of alcoholic
fetopathies (1997). J FAS Int 1:e2.
Lemoine P, Harrousseau H, Borteyru J-P, Menuet
C. 1968. Les enfants des parents alcooliques:
Anomalies observées: A propos de 127 cas.
L’Ouest Med 21:476–482.
Lemoine P, Harrousseau H, Borteyru J-P, Menuet
C. 2003. Children of alcoholic parents—
Observed anomalies: Discussion of 127
cases. Therap Drug Monit 25:132–136.
Lennestål R, Otterblad Olausson P, Källén B.
2009. Maternal use of antihypertensive
drugs in early pregnancy and delivery outcome, notably the presence of congenital
heart defects in the infants. Eur J Clin
Pharmacol 65:615–625.
Lenz W. 1988. A short history of thalidomide
embryopathy. Teratology 38:203–215.
Linares A, Zarranz JJ, Rodriguez-Alarcon J, DiazPerez JL. 1979. Reversible cutis laxa due to
maternal D-penicillamine treatment. Lancet
2:43 only.
Lipson AH, Collins F, Webster WS. 1993. Multiple congenital defects associated with maternal use of topical tretinoin. Lancet
341:1352–1353.
Loureiro KD, Kao KK, Jones KL, Alvarado S,
Chavez C, Dick L, Felix R, Johnson D,
Chambers CD. 2005. Minor malformations
characteristic of the retinoic acid embryopathy and other birth outcomes in children of
women exposed to topical tretinoin during
early pregnancy. Am J Med Genet
136A:117–121.
Marathe MR, Thomas GP. 1986. Embryotoxicity
and teratogenicity of lithium carbonate in
Wistar rat. Toxicol Lett 34:115–120.
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
Malm H, Artama M, Gissler M, Klaukka T,
Merilainen J, Nylander O, Paldan M, Palva
E, Ritvanen A, Tyrkko K. 2008. First
trimester use of ACE-inhibitors and risk of
major malformations. Reprod Toxicol
26:67.
Marecek Z, Graf M. 1976. Pregnancy in penicillamine-treated patients with Wilson’s disease.
N Engl J Med 295:841–842.
Mark-Savage P, Keen CL, Hurley LS. 1983.
Reduction by copper supplementation of
teratogenic effects of D-penicillamine. J
Nutr 113:501–510.
Meador KJ, Baker GA, Finnell RH, Kalayjian LA,
Liporace JD, Loring DW, Mawer G, Pennell
PB, Smith JC, Wolff MC, for the NSG.
2006. In utero antiepileptic drug exposure:
Fetal death and malformations. Neurology
67:407–412.
Meador KJ, Baker GA, Browning N, ClaytonSmith J, Combs-Cantrell DT, Cohen M,
Kalayjian LA, Kanner A, Liporace JD,
Pennell PB, Privitera M, Loring DW,
NEAD Study Group. 2009. Cognitive
function at 3 years of age after fetal exposure
to antiepileptic drugs. N Engl J Med
360:1597–1605.
Melnick S, Cole P, Anderson D, Herbst A. 1987.
Rates and risks of diethylstilbestrol related to
clear cell adenocarcinoma of the vagina and
cervix. N Engl J Med 316:514–516.
Meltzer HJ. 1956. Congenital abnormalities due
to attempted abortion with 4-aminopterylglutamic acid. JAMA 161:1253 only.
Menser MA, Dods L, Harley JD. 1967. A twentyﬁve year follow-up of congenital rubella.
Lancet 2:1347–1350.
Merker HJ, Franke L, Günther T. 1975. The effect
of D-penicillamine on skeletal development
of rat fetuses. Nauyn Schmiedberg’s Arch
Pharm 287:359–376.
Milham S Jr. 1985. Scalp defects in infants of
mothers treated for hyperthyroidism with
methimazole or carbimazole during pregnancy. Teratology 32:321 only.
Milham S, Elledge W. 1972. Maternal methimazole and congenital defects in children.
Teratology 5:125 only.
Miller RW. 2004. How environmental hazards in
childhood have been discovered: Carcinogens, teratogens, neurotoxicants, and others.
Pediatrics 113:945–951.
Miller E, Cradock-Watson JE, Pollack TM. 1982.
Consequences of conﬁrmed maternal
rubella at successive stages of pregnancy.
Lancet 2:781–784.
Mjolnerod OK, Dommerud SA, Rasmussen K,
Gjeruldsen ST. 1971. Congenital connective
tissue defect probably due to D-penicillamine treatment in pregnancy. Lancet
1:673–675.
Momotani N, Ito K, Hamada N, Ban Y,
Nishikawa Y, Mimura T. 1984. Maternal
hyperthyroidism and congenital malformation in the offspring. Clin Endocrinol (Oxf)
20:695–700.
Morrow J, Russell A, Guthrie E, Parsons L,
Robertson I, Waddell R, Irwin B, McGivern RC, Morrison PJ, Craig J. 2006.
Malformation risks of antiepileptic drugs in
pregnancy: A prospective study from the
UK epilepsy and pregnancy register. J
Neurol Neurosurg Psychiatry 77:193–
198.
19
Myint BA. 1984. D-penicillamine-induced cleft
palate in mice. Teratology 30:333–340.
Narotsky MG, Francis EZ, Kavlock RJ. 1994.
Developmental toxicity and structure-activity relationships of aliphatic acids, including
dose-response assessment of valproic acid in
mice and rats. Fundam Appl Toxicol
22:251–265.
Nau H. 2001. Teratogenicity of isotretinoin
revisited: Species variation and the role of
all-trans-retinoic acid. J Am Acad Dermatol
45:183–187.
Niebyl JR, Blake DA, Freeman JM, Luff RD.
1979. Carbamazepine levels in pregnancy
and lactation. Obstet Gynecol 53:139–140.
Nora JJ, Nora AH, Toews WH. 1974. Lithium,
Ebstein’s anomaly, and other congenital
heart defects. Lancet 2:594–595.
Oakley C. 1983. Pregnancy in patients with
prosthetic heart valves. Br Med J 286:
1680–1683.
Otake M, Schull WJ. 1984. In utero exposure to
A-bomb radiation and mental retardation: A
reassessment. Br J Radiol 57:409–414.
Palmer JR, Herbst AL, Noller KL, Boggs DA,
Troisi R, Titus-Ernstoff L, Hatch EE, Wise
LA, Strohsnitter WC, Hoover RN. 2009.
Urogenital abnormalities in men exposed to
diethylstilbestrol in utero: A cohort study.
Environ Health 8:37. DOI: 10.1186/1476069X-8-37.
Parkman PD. 1999. Making vaccination policy:
The experience with rubella. Clin Infect Dis
28:S140–S146.
Parkman PD, Meyer HD, Kirschstein RL, Hoops
HE. 1966. Attenuated rubella virus. I.
Development and laboratory characterization. N Engl J Med 275:569–574.
Paryani SG, Arvin AM. 1986. Intrauterine
infection with varicella-zoster virus after
maternal varicella. N Engl J Med 314:1542–
1546.
Pastaszak AL, Levy M, Schick B, Zuber C,
Feldkamp M, Gladstone J, Bar-Levy F,
Jackson E, Donnenﬁeld A, Meschino W,
Koren G. 1994. Outcome after maternal
varicella infection in the ﬁrst 20 weeks of
pregnancy. N Engl J Med 330:901–905.
Pauli RM, Haun J. 1993. Intrauterine effects of
coumarin derivatives. Dev Brain Dysfunc
6:229–247.
Pearson MA, Hoyme HE, Seaver LH, Rimsza
ME. 1994. Toluene embryopathy: Delineation of the phenotype and comparison with
fetal alcohol syndrome. Pediatrics 93:211–
215.
Philip NM, Shannon C, Winkoff B. 2002.
Misoprostol and Teratogenicity: Reviewing
the Evidence. Report of a meeting at the
Population Council.
Puhó EH, Szunyogh M, Métneki J, Czeizel AE.
2007. Drug treatment during pregnancy and
isolated orofacial clefts in Hungary. Cleft
Palate Craniofac J 44:194–202.
Raghav S, Reutens D. 2007. Neurological
sequelae of intrauterine warfarin exposure.
J Clin Neurosci 14:99–103.
REPROTOX1. 2011. Mycophenolate. Washington, DC: Reproductive Toxicology
Center. www.reprotox.org, last accessed
April 16, 2011.
Robert E, Guibaud P. 1982. Maternal valproic
acid and congenital neural tube defects.
Lancet 2:937.
20
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
Roebuck TM, Mattson SN, Riley EP. 1998. A
review of the neuroanatomical ﬁndings in
children with fetal alcohol syndrome or
prenatal exposure to alcohol. Alcohol Clin
Exp Res 22:339–344.
Rosa FW. 1986. Teratogen update: Penicillamine.
Teratology 33:127–131.
Rosa FW. 1991. Spina biﬁda in infants of women
treated with carbamazepine during pregnancy. N Engl J Med 324:674–677.
Rosas AF, Rijlaarsdam M, Buendia A, Zabal C,
Kuri J, Granados N. 2000. The adult patient
with Ebstein anomaly. Outcome in 72
unoperated patients. Medicine 79:2736.
Saji H, Yamanaka M, Hagiwara A, Ijiri R. 2001.
Losartan and fetal toxic effects. Lancet
357:363 only.
Samren EB, van Duijn CM, Christiaens GCM,
Hofman A, Lindhout D. 1999. Antiepileptic
drug regimens and major congenital abnormalities in the offspring. Ann Neurol
46:739–7746.
Samrén EB, van Duijn CM, Koch S, Hiilesmaa
VK, Klepel H, Bardy AH, Mannagetta GB,
Deichl AW, Gaily E, Granström ML,
Meinardi H, Grobbee DE, Hofman A, Janz
D, Lindhout D. 1997. Maternal use of
antiepileptic drugs and the risk of major
congenital malformations: A joint European
prospective study of human teratogenesis
associated with maternal epilepsy. Epilepsia
38:981–990.
Satgé D, Sasco AJ, Little J. 1998. Antenatal
therapeutic drug exposure and fetal/neonatal tumours: Review of 89 cases. Paediatr
Perinat Epidemiol 12:84–117.
Schaefer C, Hannemann D, Meister R, Eléfant E,
Paulus W, Vial T, Reuvers M, RobertGnansia E, Arnon J, De Santis M, Clementi
M, Rodriguez-Pinilla E, Dolivo A, Merlob
P. 2006. Vitamin K antagonists and pregnancy outcome. A multi-centre prospective
study. Thromb Haemost 95:949–957.
Schmid BP. 1984. Monitoring of organ formation
in rat embryos after in vitro exposure to
azathioprine, mercaptopurine, methotrexate
or cyclosporin A. Toxicology 31:9–21.
Schonhofer PS. 1991. Brazil: Misuse of misoprostol as an abortifacient may induce malformations. Lancet 337:1534–1535.
Schou M, Goldﬁeld MD, Weinstein MR, Villeneuve A. 1973. Lithium and pregnancy. I.
Report from the register of lithium babies.
Br Med J 2:135–136.
Schumacher H, Blake DA, Gillette JR. 1968a.
Disposition of thalidomide in rabbits and
rats. J Pharmacol Exp Ther 160:201–211.
Schumacher H, Blake DA, Gurian JM, Gillette
JR. 1968b. A comparison of the teratogenic
activity of thalidomide in rabbits and rats. J
Pharmacol Exp Ther 160:189–200.
Sever J, White LR. 1968. Intrauterine viral
infections. Annu Rev Med 19:471–486.
Shapiro L, Pastuszak A, Cutro G, Koren G. 1997.
Safety of ﬁrst-trimester exposure to topical
tretinoin: Prospective cohort study. Lancet
350:1143–1144.
Shaul WL, Hall JG. 1977. Multiple congenital
anomalies associated with oral anticoagulants. Am J Obstet Gynecol 127:191–198.
Shaw EB, Steinbach HL. 1968. Aminopterininduced fetal malformations: Survival of
infant after attempted abortion. Am J Dis
Child 115:477–482.
Sifontis NM, Coscia LA, Constantinescu S,
Lavelanet AF, Moritz MJ, Armenti VT.
2006. Pregnancy outcomes in solid organ
transplant recipients with exposure to
mycophenolate mofetil or sirolimus. Transplantation 82:1698–1702.
Skalko RG, Gold MP. 1974. Teratogenicity of
methotrexate in mice. Teratology 9:159–164.
Smithberg M, Dixit PK. 1982. Teratogenic effects
of lithium in mice. Teratology 26:239–246.
Solomon L, Abrams G, Dinner M, Berman L.
1977. Neonatal abnormalities associated
with D-penicillamine treatment during
pregnancy. N Engl J Med 296:54–55.
Song J. 2000. The use of misoprostol in obstetrics
and gynecology. Obstet Gynecol Surv
55:503–510.
Steffek AJ, Verrusio AC, Watkins CA. 1972. Cleft
palate in rodents after maternal treatment
with various lathyrogenic agents. Teratology
5:33–40.
Stern RS, Rosa F, Baum C. 1984. Isotretinoin and
pregnancy. J Am Acad Dermatol 10:851–
854.
Strandberg-Larsen K, Nielsen NR, Gronbaek M,
Andersen PK, Olsen J, Andersen AN. 2008.
Binge drinking in pregnancy and risk of fetal
death. Obstet Gynecol 111:602–609.
Streissguth AP. 1978. Fetal alcohol syndrome: An
epidemiologic perspective. Am J Epidemiol
107:467–478.
Svirsky R, Rozovski U, Vaknin Z, Pansky M,
Schneider D, Halperin R. 2009. The safety
of conception occurring shortly after
methotrexate treatment of an ectopic pregnancy. Reprod Toxicol 27:85–87.
Szabo KT. 1970. Teratogenic effect of lithium
carbonate in the foetal mouse. Nature
225:73–75.
Tabacova S, Little R, Tsong Y, Vega A, Kimmel
CA. 2003. Adverse pregnancy outcomes
associated with maternal enalapril antihypertensive treatment. Pharmacoepidemiol
Drug Saf 12:633–646.
Thiersch JB. 1952. Therapeutic abortions with
folic acid antagoinist 4-amino-pteroylglutamic acid (4 amino P.G.A.) administered by
oral route. Am J Obstet Gynecol 63:1298–
1304.
Thiersch JB, Phillips FS. 1950. Effect of 4aminopteroylglutamic acid (aminopterin)
on early pregnancy. Proc Soc Exp Biol
Med 74:204–208.
Toutant C, Lippmann S. 1979. Fetal solvents
syndrome. Lancet 1:1356.
Kesmodel U, Wisborg K, Olsen SF, Henriksen
TB, Secher NJ. 2002. Moderate alcohol
intake during pregnancy and the risk of still
birth and death in the ﬁrst year. Am J
Epidemiol 155:305–3331.
Usta IM, Nassar AH, Yunis KA, Abu-Musa AA.
2007. Methotrexate embryopathy after therapy for misdiagnosed ectopic pregnancy. Int
J Gynaecol Obstet 99:253–255.
Vajda FJ, Hitchcock A, Graham J, Solinas C,
O’Brien TJ, Lander CM, Eadie MJ. 2006.
Foetal malformations and seizure control: 52
months data of the Australian Pregnancy
Registry. Eur J Neurol 13:645–654.
Vajda FJ, Hitchcock A, Graham J, O’Brien T,
Lander C, Eadie M. 2007. The Australian
Register of Antiepileptic Drugs in Pregnancy: The ﬁrst 1002 pregnancies. Aust NZ
J Obstet Gynaecol 47:468–474.
ARTICLE
Van Dijke CP, Heydendael RJ, De Kleine MJ. 1987.
Methimazole, carbimazole, and congenital
skin defects. Ann Intern Med 106:60–61.
Vargas FR, Schuler-Faccini L, Brunoni D, Kim C,
Meloni VF, Sugayam SL, Albano L, Llerena
JC, Almeida JC, Duarte A, Calvacanti DP,
Goloni-Bertollo E, Conte A, Koren G, Addis
A. 2000. Prenatal exposure to misoprostol and
vascular disruption defects: A case–control
study. Am J Med Genet 95:302–306.
Verloes A, Frikiche A, Gremillet C, Paquay T,
Decortis T, Rigo J, Senterre J. 1990.
Proximal phocomelia and radial ray aplasia
in fetal valproic acid syndrome. Eur J Pediatr
149:266–267.
Wallpole I, Zubrick S, Pontre J. 1990. Is there a
fetal effect with low to moderate alcohol use
before or during pregnancy? J Epidemiol
Community Health 44:297–301.
Wardrop D, Keeling D. 2008. The story of the
discovery of heparin and warfarin. Br J
Haematol 141:757–763.
Warkany J, Beaudry PH, Hornstein S. 1959.
Attempted abortion with aminopterin (4aminopterylglutamic acid). AMA J Dis
Child 97:274–281.
Webster WS. 1998. Teratogen update: Congenital
rubella. Teratology 58:13–23.
Weinstein MR, Goldﬁeld MD. 1975. Cardiovascular malformations with lithium use during
pregnancy. Am J Psychiatry 132:529–531.
Wesselhoeft C. 1947. Rubella (German measles).
N Engl J Med 236:978–988.
Wilkins-Haug L. 1997. Teratogen update: Toluene. Teratology 55:145–151.
Wilkins-Haug L, Gabow PA. 1991. Toluene abuse
during pregnancy: Obstetric complications
and perinatal outcomes. Obstet Gynecol
77:504–509.
Windham GC, Fenster L, Hopkins B, Swan SH.
1995. The association of moderate maternal
and paternal alcohol consumption with
birthweight and gestational age. Epidemiology 6:591–597.
Wing DA, Millar LK, Koonings PP, Montoro
MN, Mestman JH. 1994. A comparison of
propylthiouracil versus methimazole in the
treatment of hyperthyroidism in pregnancy.
Am J Obstet Gynecol 170:90–95.
Wright TL, Hoffman LH, Davies J. 1971.
Teratogenic effects of lithium in rats.
Teratology 4:151–155.
Wyszynski DF, Nambisan M, Surve T, Alsdorf
RM, Smith CR, Holmes LB, Antiepileptic
Drug Pregnancy Registry. 2005. Increased
rate of major malformations in offspring
exposed to valproate during pregnancy.
Neurology 64:961–965.
Ylagan LR, Budorick NE. 1992. Radial ray
aplasia in utero: A prenatal ﬁnding associated
with valproic acid exposure. J Ultrasound
Med 13:408–411.
Zalzstein E, Koren G, Einarson T, Freedom RM.
1990. A case–control study on the association between ﬁrst trimester exposure to
lithium and Ebstein’s anomaly. Am J Cardiol
65:817–818.
Zamenhof S. 1985. Differential effects of antifolate on the development of brain parts in
chick embryos. Growth 49:28–33.
Zeldis JB, Williams BA, Thomas SD, Elsayed ME.
1999. S.T.E.P.S.: A comprehensive program
for controlling and monitoring access to
thalidomide. Clin Ther 21:319–330.